Bioidentical Hormones for Breast Cancer Survivors by Jeffrey Dach MD

Bioidentical Hormones for Breast Cancer Survivors

Thirty Five years ago, surgeon Steven Economou MD asked me, “Does Estrogen cause breast cancer, and does hormone replacement increase cancer recurrence in breast cancer survivors?” Back then, I did not know the answer, and neither did he. Thirty Five years later, we now have the answer.

Morning Rounds With Dr Economou

In Chicago in 1977, a Rush Hospital breast surgeon by the name of Steven Economou was making rounds with his house staff entourage of interns and residents. I was one of the interns in his group. Wearing long white coats and brandishing stethosopes, we followed Dr. Economou from room to room. Dr. Economou’s specialty was breast cancer surgery, and one of the surgical floors of Rush Hospital was filled with women either waiting for surgery or else recovering from their breast cancer operation.

Morning rounds with Steven Economou MD was a daily ritual, and as we bobbed in and out of hospital rooms, examining patients and reviewing charts, Dr Economou enjoyed stumping the house staff with difficult medical questions, as if they were small darts deftly thrown to an imaginary target on our foreheads. As if it was yesterday, I can remember one such question he asked me:
“Dr Dach, Does Estrogen cause breast cancer?”

I had just finished medical school, and I really did not know. I did not even know if the answer was known. So, as was my usual custom in those days, I made up a plausible answer based on accepted knowledge.

I assumed Dr Economou knew the answer and would provide it. To my surprise, he was silent, and offered no reply. He changed the subject and we continued on to the next case. Fast forward thirty five years, and medical science is still looking for the answer, and continues to debate this question.

Does Estrogen Cause Breast Cancer ? The Answer is – It Depends.

NO – Estrogen Does NOT Cause Breast Cancer

The results of the 11 year follow up of the Women’s Health Initiative was covered in my previous article.(1) Rather than causing breast cancer, estrogen prevented it. This study found a significant reduction in breast cancer rates for Post-Menopausal women using Estrogen Replacement (Premarin Only Arm)(To be exact, there was a 23% reduction in breast cancer in Premarin Users compared to placebo.)(1)

Yes, It Does

My previous article discussed this. The October 2010 issue of JAMA contained the 11 year follow up on the first arm of the Women’s Health Initiative which gave Prempro (Premarin plus Medroxyprogesterone) to post menopausal women. This study showed INCREASED breast cancer in the hormone treated group.(2) The hormone users had a 25 % increase in invasive breast cancer compared to placebo users. Breast cancer in the Prem-Pro users tended to more aggressive, with 78% more lymph node invasion, and greater mortality as well. (2)

Estrogen is OK, Medroxyprogesterone is NOT OK

So, here we see an obvious conclusion, that Estrogen alone does not cause breast cancer and may even be protective, while adding a Synthetic chemically altered hormone, a progestin called medroxyprogesterone, DOES CAUSE breast cancer. Not only does medroxyprogesterone cause breast cancer, these cancers tend to be more aggressive and are deadlier.

Progestins are Carcinogenic

Medroxyprogesterone is Carcinogenic

in 2000, Dr Ross at the Norris Comprehensive Cancer Center in Los Angeles published his study in the Journal of the National Cancer Institute. He says:

“This study provides strong evidence that the addition of a progestin to HRT enhances markedly the risk of breast cancer relative to estrogen use alone.”

An explanation of the carcinogenic effect of progestins is contained in an article by Dr Horowitz in 2009, ” Progestins in Hormone Replacement Therapies Reactivate Cancer Stem Cells…” (3)

Noresthisterone is Carcinogenic

Another Progestin known to be carcinogenic is Norethisterone, widely used in Finland, was the added Progestin in the HABITS study which showed (surprise) increased breast cancer in the hormone users.(4,5)

Iodine Supplementation

Spot urinary Iodine level testing, and Iodine supplementation with Iodoral. My previous article describes how iodine deficiency is a risk factor for breast cancer , and how Iodine supplementation prevents breast cancer, and can be used as adjuvant treatment.

Meridian Valley is Jonathon Wright’s lab which does urinary metabolite testing. He is the inventor of Bi-Est formula commonly used in bioidentical hormone programs. Urinary metabolite testing is useful because some women will produce harmful estrogen metabolites which can increase the risk for breast cancer. The lab test is called the 2/16 ratio. Women with higher ratios have a 42% decrease in breast cancer (9,10). Nutritional supplements such as Indole-3-carbinol and Di-Indole-Methane are known to adjust the 2/16 ratio into a higher, more favorable balance.(11) Metametrix Lab also does this testing.

Are Hormones Contra-Indicated in the Breast Cancer Survivor?

Let’s Ask William T. Creasman and Philip J. DiSaia

Both Drs. William T. Creasman and Philip J. DiSaia are highly regarded academic professors of Obstetrics and Gynecology, and authors of medical textbooks of Gynecologic Oncology and Women’s Health. They first advised in the 1980’s that hormone replacement was beneficial for the breast cancer survivor, and did not increase breast cancer recurrence. Over the many decades of their careers, they have written extensively about hormone replacement in the breast cancer survivor. Left Image: Courtesy of William T. Creasman and Philip J. DiSaia Receiving Award for Excellence in OB Gyne Surgery.

“numerous published articles have noted that recurrence rates in breast cancer survivors who chose to take HRT (Hormone Replacement) for symptom relief were very low.”… “In view of the present data, we feel it is important for women to know there are choices, and current data would suggest that there is no increased risk of recurrence with HRT.” (7)

“Several case-control and cohort studies have noted either no increased risk or actually less risk of recurrence in women taking estrogen after therapy after breast cancer. Although the general consensus is that such a recommendation is contraindicated, the data do not support this admonition.” (7A,B,C)

Dr Xydakis – Greece

“No observational or retrospective study in breast cancer survivors (whether in pre- or postmenopausal women) has shown an increased risk of tumor recurrence or increased mortality associated with HRT use.”(8)

Eva Durna MD – Australia

Also in agreement is Dr. Eva Durna from Australia.(12,13) She reported two observational studies. One in 2002 in which hormone replacement was given to post-menopausal breast cancer survivors, and one in 2004 in which hormone replacement was given to pre-menopausal (younger) breast cancer survivors. In both studies, Dr Eva Durna reports reduced mortality and reduced recurrence rates in the hormone users.(12,13)

Dr Pelin Batur of the Cleveland Clinic

Also in agreement is Dr. Pelin Batur of the Cleveland Clinic in a 2006 review of the medical literature published in Maturitas reviewing hormone replacement for breast cancer survivors.(39) Dr Pelin Batur identified seven studies which included a control group. Among 1,416 hormone replacement users, cancer reoccurrence was noted in 10.0%, while cancer recurrence was doubled (20%) for the non-hormone users. Cancer related mortality for hormone users was only 2.6% which was one third of the 7.8% cancer mortality in the non-hormone users.(39)

The Randomized Controlled Trial

The way medical research works, first a number of observational studies are done which are reported in the medical literature, always with the caveat that they are only observational.(14,15,16) As Dr Creasman reports, these are all in agreement that hormone replacement does not cause increased cancer recurrence in breast cancer survivors. Eventually the observational studies are either confirmed or refuted by randomized controlled trials (RCT’s) which are considered more definitive evidence, the Gold Standard in medical research.

Two RCT studies were done, both from Sweden. The first is called HABITS (17,18,19), and the second is called the Stockholm study (20). Both studies gave hormone replacement to breast cancer survivors in a randomized trial compared to placebo. The HABITS study showed three times greater breast cancer recurrence in the hormone treated women, while the Stockholm study showed no increased recurrence. (17-20).

How to Explain these Discrepant Findings?

The Tumor Type !

Dr Chlebowski from Brown Medical School lamented in his 2005 systematic reviewof the medical literature that the findings of the randomized controlled trials were discrepant with the observational studies. (38)Dr. Chlebowski noted that the observation studies tended to enroll women with less aggressive breast cancers that were axillary lymph node negative.(38)

It is the Progestin !

It is clear after all these years of published studies that the horse estrogen, Premarin (used alone) does not increase breast cancer risk.(1) And, while the combined ovarian hormones Estradiol and Progesterone (bioidentical) were not associated with increased breast cancer risk, use of Estradiol-alone was associated with a 1.3 fold increase in risk, as reported by Dr Fournier in the 2008 French Cohort study.(5)

As noted by Dr Fournier, adding a synthetic progestin is the major factor increasing breast cancer risk. For example, adding medroxyprogesterone resulted in a 1.48 fold increase, and Norethisterone a 2.11 increase in breast cancer. (5) Similarly, increased breast cancer risk was reported by the First Arm of the WHI using MedroxyProgesterone (2).

The ill-fated HABITS study used Norethisterone, a progestin that is known to be carcinogenic, associated with a 2-3 fold increase in breast cancer rates in Finland.(4,5) On the other hand, the more favorable Stockholm Study (20) had a larger number of women on Estrogen-Alone, as well the combination of estrogen and Medroxy-Progesterone. Medroxyprogesterone is carcinogenic, but less so than Norethisterone (4,5, 17)

In both RCT studies, a Bioidentical Progesterone should have been used, as this is non-carcinogenic and actually preventive, as demonstrated in the French Cohort study reported by Plu-Bureau in 1999 in which users of topical progesterone had a significant reduction in breast cancer risk. (35)

Previous studies in breast cancer survivors given a combination estrogen and progestin, Megace (21,22), also called Megestrol, showed protection from breast cancer recurrence, as this progestin has actually been useful in treatment of advanced breast cancer.(21,22)

This is equally true for the post-menopausal women as it is for the breast cancer survivor seeking relief from menopausal symptoms. Since the observational studies were done by knowledgeable experienced physicians who understood this fact, they chose wisely, explaining the excellent results in the many observational reports. Of course, the safest and preferred hormone combination consists of replicating the endogenous ovarian hormones, Estradiol and Progesterone with topical delivery the preferred method. This, of course, is the concept of Bioidentical Hormones.

BRCA Gene Positive Women and Hormone Replacement

Studies on BRCA gene women are most revealing.(23-27) The BRCA gene is associated with 80% lifetime risk of breast cancer.Lifetime risk for ovarian cancer are 54% for BRCA1 and 23% for BRCA2 mutation carriers BRCA Gene carrier women will frequently choose to have preventive oophorectomy (surgical removal of the ovaries) which induces surgical menopause. Therefore, it is not surprising that many of these women suffer with menopausal symptoms, and will seek relief with hormone replacement. A number of studies looking at hormone replacement in BRCA carrier women prior to or after oophorectomy show no increase in breast cancer risk from hormone replacement.

A 2008 study by Dr. Eisen followed 472 post-menopausal women with BRCA mutation on hormone replacement for menopausal symptoms. In the BRCA gene women who took Estrogen-Alone, they found a 50% reduction in breast cancer rates.(23) Again, results for Estrogen-Alone were superior to the estrogen-progestin combination. Natural progesterone (bioidentical) is preferable to the synthetic progestins.

The experience with hormone replacement in BRCA gene carriers again suggests that Estrogen does not cause breast cancer, and is actually preventive. Rather, we know from current research that breast cancer is caused by oxidative damage to the DNA of breast cells. The BRCA gene mutation does exactly this, it causes malfunction of the anti-oxidant system. leading to oxidative damage to the DNA of the breast cell. Breast cancers in BRCA gene women tend to be triple negative , ie. estrogen, and progesterone receptor negative which are non-responsive to ovarian ablation.

Selenium supplementation has been found beneficial for BRCA carriers. Dr. Dziaman from Poland published a study in Nov 2009 looking at DNA damage in BRCA gene carriers. Here is a pdf of the article:Selenium_Reduced_DNA_Damage_BRCA_Carriers_2009.
Dr. Dziaman measured serum and urinary products of DNA oxidation with and without selenium supplementation, finding that damaged DNA products were higher in women with BRCA mutations, and were reduced by selenium supplementation. Their results suggest that BRCA1 deficiency contributes to Oxidative Damage and Breaks in cellular DNA, which may be responsible for cancer development. In addition, selenium supplementation is beneficial because it protects from oxidative DNA damage.

Strong Evidence for a Selenium as Preventive Agent – Kowalska

A study of BRCA gene carriers from Kowalska in Poland in 2005 provides strong evidence for selenium as a preventive agent.
Here is a pdf of the article:Chromosome_Breakage_BRCA1_Normalized_by_Selenium_Kowalska
Fifty five women with the BRCA1 gene mutation were supplemented with 275 µg of sodium selenite, daily for 8 weeks. The amount of DNA damage was assessed from blood lymphocytes showing BRCA gene carriers had twice the DNA damage compared to their normal siblings. However, Selenium supplementation given to BRCA gene carriers reduced the DNA damage to normal levels found in their siblings. A second larger study reported by Kowalska in 2006 verified that selenium supplementation indeed reduces cancer in women with the BRCA1 gene. After two years of selenium supplementation, expected BRCA1-associated cancers were reduced by half. For more: see my article on selenium.

Ovarian Ablation as Treatment for Breast Cancer

Breast cancer can occur in the younger pre-menopausal woman. Most commonly this is an indolent form of cancer called DCIS (ductal carcinoma in situ) which has a very good prognosis. However, another form of cancer (infiltrating ductal cancer) can be very aggressive in this age group with poor prognosis regardless of treatment. This variety tends to be estrogen receptor positive, and highly aggressive with a median survival of 26 months. (27-34) In this type of highly aggressive Estrogen-Receptor-Positive breast cancer in younger pre-menopausal women the mainstream medical treatment is ovarian ablation (either surgical or drug induced) to eliminate endogenous Estrogen.(28)

In 2,100 pre-menopausal estrogen receptor positive breast cancer patients, ovarian ablation improved 15 year survival from 46% to 52%. (29) This is a six per cent absolute benefit, which is quite disappointing.(29) This again underscores the aggressive nature of this variety of breast cancer, and the futility of mainstream treatment.

Obviously, in this scenario, hormone replacement would be contra-indicated. For women over the age of 50, ovarian ablation was of no benefit regardless of tumor receptor status.(29) So, patient age, tumor grade and hormone receptor status, and disease free years since diagnosis and treatment are important considerations when considering whether or not to offer hormone replacement program for the breast cancer survivor. (27-34)

Family History of Breast Cancer

The benefits of hormone replacement extend to women with a family history of breast cancer. A 1997 study in Iowa followed 41,800 women for 8 years. Those women using hormone replacement who had a history of breast cancer in a family member still had a 50% reduction in over all mortality compared to non-users.(36) There was a slight increase in breast cancer in the hormone users in this observational study. However this was not statistically significant. (36)

Opposing Opinions – Confusing Progestins with Progesterone

To be fair, a number mainstream authors oppose Dr. Creasman’s opinion such as Dr Labriola in a 2009 rebuttal letter (40) Again, the opposing views are usually based on the confusion of chemically altered progestins which are known to be carcinogenic, with the ovarian hormone, progesterone. Progestins are not progesterone. They have an entirely different chemical structure and different biological activity profile.

As you read through the medical literature you will find a common mistake. Many of the reference articles on this topic use mistaken terminology, referring to a “progestin” hormone as “progesterone” which it is not.(7a)(23) For example Dr Andrea Eisen’s BRCA gene article says that the first arm of the WHI used a combination pill consisting of Estrogen and Progesterone which increased breast cancer risk. (23)

This is entirely incorrect, as the WHI actually used Premarin and Provera (medroxyprogesterone) a progestin. Progestin use is associated with increased breast cancer, while Progesterone use is not. This mistake permeates the women’s hormone literature explaining the many discrepancies in findings and opinions. So when you see the word progesterone in a medical report, you have to ask yourself, does the author really mean “progesterone”, or was in fact a “progestin” given to these women?

Unfortunately, as yet, after all these years, there are still no randomized trials of postmenopausal hormone replacement with commonly used bioidentical hormone preparations such as topical Bi-Est (80% estriol and 20% estradiol) and topical Progesterone. We urgently need RCT studies of bioidentical hormone therapies in breast cancer survivors as well.

Update July 2014: Read this interview with Dr. Rajkumar Lakshmanaswamy, PhD Research Director of the Center of Excellence in Cancer Research.at Texas Tech University.
Quote from Interview: Dr. Lakshmanaswamy says:

The current treatment for women after hormone-sensitive breast cancer is estrogen-blocking aromatase inhibitors, a nearly opposite treatment to the hormone therapy we studied. We were surprised to find that not only did the right combination of hormones provide better outcomes in terms of cardiovascular and bone measures, but were also more effective against breast cancer.” end quote.

Dr. Lakshmanaswamy used a mouse model which mimiced breast cancer in humans. In his study menopausal mice were injected with xenografted human breast cancer cells. These breast cancer mice were then treated with Bioidentical Hormones (estradiol, progesterone,testosterone) showing a dramatic reduction in tumor size, with better results compared to conventional aromatase treatment. See study pdf of publication here: Bioidentical_hormones_postmenopausal_mouse_Rajkumar2014

Steven G. Economou was adept with both scalpel and pen, chairing the surgery department at what is now Rush University Medical Center and writing dozens of medical articles and doodling abstract figures that illustrated his self-published books. Dr. Economou, 84, died Saturday, April 7, at Rush North Shore Medical Center in Skokie of complications from illnesses including Parkinson’s disease, said his wife, Kathryn, who goes by the name “Kitty.”

Following the initial report of results from the WHI trial,1 a substantial decrease in breast cancer incidence occurred in the United States, which was attributed24-25 to the marked decrease in postmenopausal hormone therapy use that occurred after publication of the trial results.26 The adverse influence of estrogen plus progestin on breast cancer mortality suggests that a future reduction in breast cancer mortality in the United States may be anticipated as well.

In conclusion, use of estrogen plus progestin increases the incidence of breast cancer, and the cancers are more commonly node-positive. Mortality data analyses suggest that breast cancer mortality may also be increased.

An increased risk of invasive, estrogen receptor-positive (ER+) breast cancer in the combined estrogen plus progestin arm of the Women’s Health Initiative menopausal hormone replacement therapy (HRT) trial was in large part responsible for stopping the study prematurely in 2002. Subsequent studies offered several possibilities to explain how addition of progestins to estrogens increases the risk of breast cancer. The authors of this report offer a hypothesis for the increased risk based on their research and that of other investigators.

A rare small tumorigenic subpopulation of estrogen receptor-negative, progesterone receptor-negative cancer stem cells is present in experimental ER+, progesterone receptor-positive human breast cancers.
Progestins but not estrogens act on the ER+, progesterone receptor-positive differentiated cells (especially in small nascent tumor colonies) to reactivate and revert to the more primitive estrogen receptor-negative, progesterone receptor-negative stem cells without requiring proliferation. The authors propose that a reservoir of occult, undetected, preinvasive breast cancer or dormant breast cancer stem cells is present before the start of estrogen plus progestin therapy in some women.

Autopsy data of women over 40 years of age who did not have known breast cancer during life showed that the median prevalence of invasive breast cancer at death was 1.3% (range: 0%-1.8%), and the median prevalence of ductal carcinoma in situ was 8.9% (range: 0%-14%). Estrogens are not involved in the activation process, but once receptors are reacquired, they can act through their mitogenic properties to expand the tumor cell population.

The authors believe that improved screening methods are needed to detect occult, possibly dormant, breast cancers before initiation of hormone replacement therapy. If the hypothesis is correct, women with such preexisting malignancies should be excluded from regimens containing systemic progestins.

Do the dose or route of administration of norethisterone acetate as a part of hormone therapy play a role in risk of breast cancer: National-wide case-control study from Finland by Heli Lyytinen1, Tadeusz Dyba2, Eero Pukkala2,3, Olavi Ylikorkal

It is established that the use of postmenopausal estrogen–progestagen therapy (EPT) is associated with a higher risk elevation for breast cancer than is the sole use of estrogen.1–3 This may imply that progestagen, alone or in combination with estrogen, is more crucial for the possible initiation and/or growth of breast cancer than is estrogen. Modern recommendations advocate the use of the lowest effective doses, and then the main focus has been placed on the dose of estrogen.4–9 Indeed, no data exist on the daily dose-dependence between progestagen and the risk for breast cancer, although the higher risks associated with continuous EPT rather than sequential EPT use may hint at such a dependence.1, 10

In Finland, the most common progestagen as a part of EPT is norethisterone acetate (NETA), which can be given both orally and transdermally.3

The use of a “low” dose NETA-regimen was associated with an increased risk for breast cancer already in 3 years of use (1.94; 1.39–2.70)

the aim of our study was to assess the effect of post-diagnostic serum 25-hydroxyvitamin D [25(OH)D] concentrations on overall survival and distant disease-free survival.

METHODS: We conducted a prospective cohort study in Germany including 1,295 incident postmenopausal breast cancer patients aged 50-74 years. Patients were diagnosed between 2002 and 2005 and median follow-up was 5.8 years.

7) http://www.cancernetwork.com/breast-cancer/content/article/10165/1486356
Hormone Replacement and Breast Cancer Risk: Reconsidering the Data by By William T. Creasman, MD Department of Obstetrics and Gynecology Medical University of South Carolina Charleston, South Carolina and Philip J. DiSaia, MD Department of Obstetrics and Gynecology University of California, Irvine Irvine, California |

The rationale for the alternative was the fact that in one large study, the women who took conventional hormone replacement therapy (HRT) preparations had a higher risk for breast cancer, and therefore, similar preparations could not be used in breast cancer survivors with vasomotor symptoms.

The authors justified that statement by citing the 2002 Women’s Health Initiative (WHI) study.[1] This study compared estrogen plus progestin with a placebo. Another prospective randomized group mentioned by the authors received estrogen alone compared to a placebo, but this study was not referenced.

We remain amazed at the literature that incriminates estrogen/progestin and estrogen alone, quoting the 2002 WHI article for estrogen/progestin even though there have been over 100 articles from the WHI since then, in which a significant amount of the 2002 data have been temporized or shown not to support the conclusions of the 2002 publication. Many articles have been written severely criticizing the methodology of the WHI study, including eligibility, surveillance, presentation of nonadjudicated data, and certainly the age of the participants, to name a few. We are not writing to reiterate those faults, but to suggest that recent WHI data do not note an increase in breast cancer risk.

The 2002 article stated that the hazard ratio (HR) for estrogen plus progestin was 1.26 (95% confidence interval [CI] = 1.0–1.59), which is not statistically significant but was the reason for stopping the study. In a 2003 article, the HR was 1.24 (95% CI = 1.01–1.54), now barely significant as the number of breast cancers had increased since the 2002 publication.[2]

In the 2006 publication on estrogen plus progestin, the adjusted HR was 1.20 (95% CI = 0.94–1.53).[3] Although the WHI investigators may have been under significant pressure to publish data from the study, we suggest that it may have been reported prematurely, and the bulk of the patients were elderly women upon enrollment. More women who were 50 to 59 years of age, or less than 10 years from menopause should have been enrolled. In truth, how many 70-year-old women are placed on HRT for the first time?

In the 50- to 59-year-old age group, not only was there no increased risk, but the HR was actually less than 1.[4] In their rather detailed article on younger women with cardiovascular disease, the investigators commented that women less than 10 years since menopause had an HR of 1.19 (95% CI = 0.84–1.70) for breast cancer.[4] This is certainly not statistically significant.

In 2004, the data on estrogen alone was presented for the first time (a prospective randomized study of about 10,000 women compared to over 16,000 women in the estrogen/progestin study). The HR for breast cancer was 0.77 (95% CI = 0.59–1.01).[5] In the 50- to 59-year-olds, the HR was 0.72 (95% CI = 0.43–1.21). In 2006, a 7.1-year follow-up of estrogen and breast cancer risk was published. If a woman had no prior replacement therapy history, her HR was 0.76 (95% CI = 0.58–0.99), her risk for ductal cancer was 0.71 (95% CI = 0.52–0.99), and if she was adherent in regard to taking her medication, the HR was 0.67 (95% CI = 0.47–0.97).[6] Therefore, we question the assumption that estrogen/progestin and estrogen alone increase the risk of breast cancer using the studies that the commentary referenced.

Historical Perspective

That being the case, why is traditional HRT contraindicated in women who have had breast cancer? From a historical perspective, for many years estrogen was used as primary treatment for postmenopausal women with recurrent or metastatic breast cancer. In the 1970s and early 1980s, several prospective randomized studies compared estrogen with tamoxifen(Drug information on tamoxifen) in such women. The results were similar.[7]

Since alternatives, as noted in the commentary, are not very effective, numerous published articles have noted that recurrence rates in breast cancer survivors who chose to take HRT for symptom relief were very low. Yes, these were retrospective studies with built-in bias. One bias may come from the woman herself, as she chooses to take the hormones.

Several case control and cohort studies have compared HRT with such controls, and in over 1,200 cases and 3,800 controls, there was twice as many recurrences in the controls as in those on hormones.[6]

Two prospective randomized studies have compared hormones with controls. Both of these studies originated in Sweden.

In the HABITS study, 442 women were randomized to receive hormones or no hormones for 2 years. The initial report in 2004 noted an HR of 3.3 (95% CI = 1.5–7.4), and the study was stopped.[9] A 4-year follow-up noted an adjusted HR of 2.2 (95% CI = 1.0–5.0).[10]

The other study (the Stockholm trial) randomized 359 breast cancer women to 5 years of hormones or no hormones. Data reported in 2008 noted an HR of 0.8 (95% CI = 0.35–1.9).[11] The investigators found no difference in breast cancer deaths between the hormone and no-hormone groups in either study.

Importance of Options

These data on HRT in breast cancer patients are not well disseminated. In many instances, women are told that HRT is absolutely contraindicated, yet we are unaware of any clinical data to substantiate that statement. In view of the present data, we feel it is important for women to know there are choices, and current data would suggest that there is no increased risk of recurrence with HRT. Once women are given data and they have made a decision, we as health-care professionals should support them and not criticize that decision.
Why is HRT contraindicated in a 50-year-old newly menopausal breast cancer survivor who was successfully treated for her cancer at 40 years of age? Hasn’t she been getting endogenous estrogen for the last 10 years? This question and others make these authors question the tenet that postmenopausal estrogen therapy is always contraindicated in a woman who has had breast cancer.

The role of female hormones in estrogen-dependent cancers has been debated for years. This is particularly true of breast cancer. Retrospective, case, and cohort control studies usually have suggested no influence. The Women’s Health Initiative study in 2002, a prospective double-blind study, noted an increased risk of breast cancer if estrogen plus progesterone was given.

(Dr Dach note: the above should read Premarin and the progestin, Provera, not estrogen and progesterone)

In the estrogen-only arm of that study, a decreased (not significant) risk of breast cancer was noted. With this controversy, can estrogen be given safely to a woman who has been treated for breast cancer? The relation between endometrial cancer and unopposed estrogen is well established. With clear-cut evidence of this relation, is there evidence to suggest a role for replacement therapy in women who have been treated for endometrial cancer?

RECENT FINDINGS: Several case-control and cohort studies have noted either no increased risk or actually less risk of recurrence in women taking estrogen after therapy after breast cancer. Although the general consensus is that such a recommendation is contraindicated, the data do not support this admonition. The current data suggest that replacement therapy can be given to the woman who has been treated for endometrial cancer.

SUMMARY:“There seems to be little if any risk in giving hormone replacement therapy to women who have had breast or endometrial cancer. There are no data to suggest that hormone replacement therapy is contraindicated in women who have been treated for cervical or ovarian cancer.”

Ever since Professor William T. Creasman suggested the use of hormone replacement therapy in breast cancer survivors in the early 1980s, interest in this field has been guarded but present. Prescribing HRT to breast cancer survivors was initially thought of as being outrageous. Yet even then with experience in HRT spanning a good three decades, and with the breast cancer epidemic, so confidently predicted, then as it is now never actually materializing, doctors working in the field had started to question the conventional wisdom. The debate on whether to treat breast cancer survivors with HRT has been revisited from time to time as there has been a powerful demand for a solution for such symptomatic women.

The role of female hormones in estrogen-dependent cancers has been debated for years. This is particularly true of breast cancer. Retrospective, case, and cohort control studies usually have suggested no influence. The Women’s Health Initiative study in 2002, a prospective double-blind study, noted an increased risk of breast cancer if estrogen plus progesterone was given. In the estrogen-only arm of that study, a decreased (not significant) risk of breast cancer was noted. With this controversy, can estrogen be given safely to a woman who has been treated for breast cancer? The relation between endometrial cancer and unopposed estrogen is well established. With clear-cut evidence of this relation, is there evidence to suggest a role for replacement therapy in women who have been treated for endometrial cancer?

RECENT FINDINGS:Several case-control and cohort studies have noted either no increased risk or actually less risk of recurrence in women taking estrogen after therapy after breast cancer. Although the general consensus is that such a recommendation is contraindicated, the data do not support this admonition. The current data suggest that replacement therapy can be given to the woman who has been treated for endometrial cancer.

SUMMARY:There seems to be little if any risk in giving hormone replacement therapy to women who have had breast or endometrial cancer. There are no data to suggest that hormone replacement therapy is contraindicated in women who have been treated for cervical or ovarian cancer

It is well known that women with breast cancer who undergo therapies beyond the surgical intervention (adjuvant chemotherapy, hormone therapy, or both) often suffer from the lack of estrogen, manifesting as climacteric symptoms in either treated premenopausal or postmenopausal women. Although HRT (hormone replacement therapy) is traditionally viewed as a contraindication in women with a history of breast cancer, more women are willing to receive HRT for symptom relief.

“No observational or retrospective study in breast cancer survivors (whether in pre- or postmenopausal women) has shown an increased risk of tumor recurrence or increased mortality associated with HRT use.”

Nevertheless, because these studies are retrospective and different in terms of lymph node status, estrogen receptor (ER) status, and type of HRT used, firm conclusions on potential HRT use cannot be safely drawn. The few prospective studies appear controversial possibly due to differences in the studies’ design. A potential scheme for possible HRT use in selected breast cancer survivors with severe climacteric symptoms is suggested. The duration of HRT use is debatable because there is insufficient evidence at present.

However, the available data suggest that 3-year and possibly 5-year HRT use may be safe.

In summary, while HRT cannot currently be recommended as first-line therapy, it may still be of benefit in the management of selected early stage breast cancer survivors with refractory climacteric symptoms after a well-informed decision and an individualized risk benefit discussion.

Experimental and clinical evidence suggests that 16alpha-hydroxylated estrogen metabolites, biologically strong estrogens, are associated with breast cancer risk, while 2-hydroxylated metabolites, with lower estrogenic activity, are weakly related to this disease. This study analyzes the association of breast cancer risk with estrogen metabolism, expressed as the ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone, in a prospective nested case-control study. Between 1987 and 1992, 10,786 women (ages 35-69 years) were recruited to a prospective study on breast cancer in Italy, the “Hormones and Diet in the Etiology of Breast Cancer” (ORDET) study. Women with a history of cancer and women on hormone therapy were excluded at baseline. At recruitment, overnight urine was collected from all participants and stored at -80 degrees C. After an average of 5.5 years of follow-up, 144 breast cancer cases and four matched controls for each case were identified among the participants of the cohort.

Among premenopausal women, a higher ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone at baseline was associated with a reduced risk of breast cancer: women in the highest quintile of the ratio had an adjusted odds ratio (OR) for breast cancer of 0.58 [95% confidence interval (CI) = 0.25-1.34]. The corresponding adjusted OR in postmenopausal women was 1.29 (95% CI = 0.53-3.10). Results of this prospective study support the hypothesis that the estrogen metabolism pathway favoring 2-hydroxylation over 16alpha-hydroxylation is associated with a reduced risk of invasive breast cancer risk in premenopausal women.

Estrogens are known for their proliferative effects on estrogen-sensitive tissues resulting in tumorigenesis. Results of experiments in multiple laboratories over the last 20 years have shown that a large part of the cancer-inducing effect of estrogen involves the formation of agonistic metabolites of estrogen, especially 16-alpha-hydroxyestrone. Other metabolites, such as 2-hydroxyestrone and 2-hydroxyestradiol, offer protection against the estrogen-agonist effects of 16-alpha-hydroxyestrone. An ELISA method for measuring 2- and 16-alpha-hydroxylated estrogen (OHE) metabolites in urine is available and the ratio of urinary 2-OHE/16-alpha-OHE (2/16-alpha ratio) is a useful biomarker for estrogen-related cancer risk. The CYP1A1 enzyme that catalyzes 2-hydroxyestrone (2-OHE1) formation is inducible by dietary modification and supplementation with the active components of cruciferous vegetables, indole-3-carbinol (I-3-C), or diindolylmethane (DIM). Other dietary components, especially omega-3 polyunsaturated fatty acids and lignans in foods like flax seed, also exert favorable effects on estrogen metabolism. Thus, there appear to be effective dietary means for reducing cancer risk by improving estrogen metabolism. This review presents the accumulated evidence to help clinicians evaluate the merit of using tests that measure estrogen metabolites and using interventions to modify estrogen metabolism.

To determine any association between hormonal replacement therapy (HRT) usage and breast cancer recurrence and survival rates in women who were premenopausal at the time of diagnosis of breast cancer.
METHODS:

The study group comprised 524 women who were diagnosed with breast cancer when they were premenopausal. Of these, 277 women reached menopause before recurrence of the disease, being lost to follow-up, or reaching the end of the study. In this group, 119 women took HRT to control menopausal symptoms. The majority took combined continuous estrogen-progestin treatment. Times from diagnosis to cancer recurrence or new breast cancer, to death from all causes, and to death from primary tumor were compared between HRT users and non-users.

RESULTS:Women who used HRT after their menopause had an adjusted relative risk of recurrence or new breast cancer of 0.75 (95% confidence interval (CI), 0.29-1.95) compared to that of non-users.The relative risk of death from all causes was 0.36 (95% CI, 0.11-1.16) and that of death from primary tumor was 0.24 (95% CI, 0.05-1.14).

CONCLUSION: HRT use in women who were premenopausal at the diagnosis of primary invasive breast cancer is not associated with worse outcomes in terms of breast cancer recurrence or mortality.

To determine whether hormone replacement therapy (HRT) after treatment for breast cancer is associated with increased risk of recurrence and mortality.

DESIGN: Retrospective observational study.

PARTICIPANTS AND SETTING: Postmenopausal women diagnosed with breast cancer and treated by five Sydney doctors between 1964 and 1999.

OUTCOME MEASURES:

Times from diagnosis to cancer recurrence or new breast cancer, to death from all causes and to death from primary tumour were compared between women who used HRT for menopausal symptoms after diagnosis and those who did not. Relative risks (RRs) were determined from Cox regression analyses, adjusted for patient and tumour characteristics.

RESULTS: 1122 women were followed up for 0-36 years (median, 6.08 years); 154 were lost to follow-up. 286 women used HRT for menopausal symptoms for up to 26 years (median, 1.75 years).

HRT has long been contraindicated in women who have—or have had—breast cancer. Here, the author examines the effects estrogen has on the breast and reviews several studies that suggest HRT actually may be of benefit to these women.

WILLIAM CREASMAN, MD – Dr. Creasman is the J. Marion Sims Professor of OBG at the Medical University of South Carolina in Charleston.

We compared the risk of cancer recurrence and all-cause mortality among users and nonusers of estrogen replacement therapy (ERT) after the diagnosis of breast cancer.

STUDY DESIGN: This was a systematic review of original research. Eligible studies were reviewed by 2 investigators who independently extracted data from each study according to a predetermined form and assessed each study for validity on standard characteristics. Meta-analyses were performed with Review Manager 4.1 to provide a summary of relative risks of cancer recurrence and mortality.

POPULATION:Studies included 717 subjects who used hormone replacement therapy (HRT) at some time after their diagnosis of breast cancer, as well as 2545 subjects who did not use HRT.

Although limited by observational design, existing research does not support the universal withholding of ERT from well-informed women with a previous diagnosis of low-stage breast cancer. Long-term randomized controlled trials are needed.

In this trial,there was no significant difference in risk between combined preparations,oestrogen-only preparations and other preparations (suchastibolone) [71]. The Stockholm trial also randomised survivors to treatment with HRT or no HRT ;in this study there was no increased risk of recurrence in women in
the HRT arm. One possible explanation for this is the higher pro-
portion of women taking oestrogen-only preparations rather than continuous combined hormone preparations,indicating that the
oestrogen-only preparations may be less hazardous in this group of women [72].

Based on these studies,systemic HRT is not recommended in breastcancer survivors.

Hormone replacement therapy (HT) is known to increase the risk of breast cancer in healthy women, but its effect on breast cancer risk in breast cancer survivors is less clear. The randomized HABITS study, which compared HT for menopausal symptoms with best management without hormones among women with previously treated breast cancer, was stopped early due to suspicions of an increased risk of new breast cancer events following HT. We present results after extended follow-up.

METHODS: HABITS was a randomized, non-placebo-controlled noninferiority trial that aimed to be at a power of 80% to detect a 36% increase in the hazard ratio (HR) for a new breast cancer event following HT. Cox models were used to estimate relative risks of a breast cancer event, the maximum likelihood method was used to calculate 95% confidence intervals (CIs), and chi(2) tests were used to assess statistical significance, with all P values based on two-sided tests. The absolute risk of a new breast cancer event was estimated with the cumulative incidence function. Most patients who received HT were prescribed continuous combined or sequential estradiol hemihydrate and norethisterone.

RESULTS:

Of the 447 women randomly assigned, 442 could be followed for a median of 4 years. Thirty-nine of the 221 women in the HT arm and 17 of the 221 women in the control arm experienced a new breast cancer event (HR = 2.4, 95% CI = 1.3 to 4.2). Cumulative incidences at 5 years were 22.2% in the HT arm and 8.0% in the control arm. By the end of follow-up, six women in the HT arm had died of breast cancer and six were alive with distant metastases. In the control arm, five women had died of breast cancer and four had metastatic breast cancer (P = .51, log-rank test).

CONCLUSION:

After extended follow-up, there was a clinically and statistically significant increased risk of a new breast cancer event in survivors who took HT.

In the 1990s, two randomised clinical trials started in Scandinavia addressing whether hormone replacement therapy (HRT) is safe for women with previous breast cancer. We report the findings of the safety analysis in HABITS (hormonal replacement therapy after breast cancer–is it safe?), an open randomised clinical trial with allocation to either HRT or best treatment without hormones. The main endpoint was any new breast cancer event. All analyses were done according to intention-to-treat. Until September, 2003, 434 women were randomised; 345 had at least one follow-up report. After a median follow-up of 2.1 years, 26 women in the HRT group and seven in the non-HRT group had a new breast-cancer event. All women with an event in the HRT group and two of those in the non-HRT group were exposed to HRT and most women had their event when on treatment. We decided that these findings indicated an unacceptable risk for women exposed to HRT in the HABITS trial, and the trial was terminated on Dec 17, 2003.

In 1997 two independent randomized clinical trials, Hormonal Replacement Therapy After Breast Cancer–Is It Safe? (HABITS; 434 patients) and the Stockholm trial (378 patients), were initiated in Sweden to compare menopausal hormone therapy with no menopausal hormone therapy after diagnosis of early-stage breast cancer. Much of the design of both studies was similar; however, a goal of the Stockholm protocol, not shared with the HABITS trial, was to minimize the use of progestogen combined with estrogen. The HABITS trial was prematurely stopped in December 2003, because, at a median follow-up of 2.1 years, the risk for recurrence of breast cancer among patients receiving menopausal hormone therapy was statistically significantly higher (relative hazard [RH] = 3.3, 95% confidence interval [CI] = 1.5 to 7.4) than among those receiving no treatment. In the Stockholm trial, however, at a median follow-up of 4.1 years, the risk of breast cancer recurrence was not associated with menopausal hormone therapy (RH = 0.82, 95% CI = 0.35 to 1.9). Statistically significant heterogeneity in the rate of recurrence was observed (P = .02; two-sided likelihood-ratio test) between the two studies, indicating that chance may not be the only explanation. Doses of estrogen and progestogen and treatment regimens for menopausal hormone therapy may be associated with the recurrence of breast cancer.

Most physicians believe that estrogen replacement therapy is contraindicated once a patient is diagnosed with breast cancer. Recently, several studies have shown that estrogen replacement therapy may be safely used in patients with early breast cancer that has been treated successfully. These women can have severe menopausal symptoms and are at risk for osteoporosis. We reviewed the current status of women in our practice with breast cancer who received estrogen replacement therapy, who did not receive hormone replacement therapy, and who did not receive estrogenic hormone replacement therapy.

STUDY DESIGN:The study group consisted of 123 women (mean age, 65.4 +/- 8.85 years) who were diagnosed with breast cancer in our practice, including 69 patients who received estrogen replacement therapy for < or = 32 years after diagnosis. The comparative groups were 22 women who used nonestrogenic hormones for < or = 18 years and 32 women who used no hormones for < or = 12 years. The group who did not receive estrogenic hormone replacement therapy received androgens with or without progestogens (such as megestrol acetate). Of the 63 living hormone users, 56 women are still being treated in our clinic, as are 15 of the 22 subjects who receive nonestrogenic hormone replacement therapy. Follow-up was done through the tumor registry at University Hospital; those patients whose tumor records were not current were contacted by telephone.

RESULTS:There were 18 deaths in the 123 patients: 6 patients who received estrogen replacement therapy (8.69%), 2 patients who received nonestrogenic hormone replacement therapy (9.09%), and 10 patients who received no hormone replacement therapy (31.25%).

Of the 18 deaths, 9 deaths were from breast cancer (mortality rate, 7.3%); 3 deaths were from lung cancer; 1 death was from endometrial cancer; 1 death was from myocardial infarction; 1 death was from renal failure; and 3 deaths were from cerebrovascular accidents. The 9 deaths from breast cancer included one patient who received nonestrogenic hormone replacement therapy (mortality rate, 4.5%), 6 patients who received no hormone replacement therapy (mortality rate, 11.3%), and 2 patients who received estrogen replacement therapy (mortality rate, 4.28%). The 9 non-breast cancer deaths included 4 patients who received estrogen replacement therapy (endometrial cancer [1 death], lung cancer [1 death], cerebrovascular accident [1 death], and renal failure [1 death]), 1 patient who did not receive estrogenic hormone replacement therapy group (myocardial infarction), and 4 patients who used no hormones (lung cancer, 2 deaths; stroke, 2 deaths). Carcinoma developed in one patient in the estrogen replacement therapy group in the contralateral breast after 4 years of hormone replacement therapy; she is living and well 2.5 years later with no evidence of disease. Metastatic breast cancer developed in one patient after 8 years of hormone replacement therapy; she is living with disease.

CONCLUSION: Estrogen replacement therapy apparently does not increase either the risk of recurrence or of death in patients with early breast cancer. These patients may be offered estrogen replacement therapy after a full explanation of the benefits, risks, and controversies.

OBJECTIVE: We sought to review the status of patients with breast cancer who were treated with estrogen replacement therapy and compare the results with those of nonestrogenic hormone users and women not treated with hormone replacement.

STUDY DESIGN: The study group consisted of 76 patients with breast cancer, including 50 using estrogen replacement for up to 32 years, 8 using nonestrogenic hormone replacement for up to 6 years and followed for up to 11 years, and 18 using no hormones for up to 10 years. In addition to estrogen use, 40 of the 50 hormone users were treated with androgens, usually in the form of implantation of testosterone pellets. Forty-five subjects were also given progestogens, usually megestrol acetate 20 to 40 mg for 10 to 25 days each month. The 8 nonestrogen hormone users were treated with various combinations of testosterone pellets, tamoxifen, and progestogens. Forty-two of the 50 estrogen users are still being treated in our clinic, as are 2 of the 8 subjects using nonestrogen hormone. Follow-up was done through the tumor registry at University Hospital, and those whose tumor records were not current were telephoned.

RESULTS: Of the 50 estrogen users, 3 have died (a mortality rate of 6%), and the rest have been followed for 6 months to 32 years, with a mean duration of follow-up of 83.3 +/- 8.81 months. One of the 8 nonestrogen hormone users has died (a mortality rate of 12.5%), and the rest have been followed for 2 to 11 years, with a mean duration of follow-up of 72.0 +/- 5. 93 months. Six of the 18 women not using hormone replacement have died (a mortality rate of 33.3%), and the rest have been followed for 6 months to 10 years, with a mean duration of follow-up of 50.5 +/- 6.01 months.

CONCLUSION: Estrogen replacement therapy apparently does not increase either recurrences or mortality rates. Adding progestogens (Megace) may even decrease recurrences. Women with early breast cancer should be offered hormone replacement therapy after a full explanation of the benefits, risks, and controversies.

———————————–BRCA GENE

2008

HRT in BRCA GENE women after OOPhorectomy or Menopause-
less BR CA with HRT –

Hormone therapy (HT) is commonly given to women to alleviate the climacteric symptoms associated with menopause. There is concern that this treatment may increase the risk of breast cancer. The potential association of HT and breast cancer risk is of particular interest to women who carry a mutation in BRCA1 because they face a high lifetime risk of breast cancer and because many of these women take HT after undergoing prophylactic surgical oophorectomy at a young age.

We conducted a matched case-control study of 472 postmenopausal women with a BRCA1 mutation to examine whether or not the use of HT is associated with subsequent risk of breast cancer. Breast cancer case patients and control subjects were matched with respect to age, age at menopause, and type of menopause (surgical or natural). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with conditional logistic regression. Statistical tests were two-sided.

RESULTS:In this group of BRCA1 mutation carriers, the adjusted OR for breast cancer associated with ever use of HT compared with never use was 0.58 (95% CI = 0.35 to 0.96; P = .03). In analyses by type of HT, an inverse association with breast cancer risk was observed with use of estrogen only (OR = 0.51, 95% CI = 0.27 to 0.98; P = .04); the association with use of estrogen plus progesterone was not statistically significant (OR = 0.66, 95% CI = 0.34 to 1.27; P = .21).
CONCLUSION:Among postmenopausal women with a BRCA1 mutation, HT use was not associated with increased risk of breast cancer; indeed, in this population, it was associated with a decreased risk.

Purpose Bilateral prophylactic oophorectomy (BPO) is widely used for cancer risk reduction in women with BRCA1/2 mutations. Many premenopausal women choose to take hormone replacement therapy (HRT) after undergoing BPO to abrogate immediate symptoms of surgically-induced menopause. Thus, we evaluated whether the breast cancer risk reduction conferred by BPO in BRCA1/2 mutation carriers is altered by use of post-BPO HRT. Methods We identified a prospective cohort of 462 women with disease-associated germline BRCA1/2 mutations at 13 medical centers to evaluate breast cancer risk after BPO with and without HRT. We determined the incidence of breast cancer in 155 women who had undergone BPO and in 307 women who had not undergone BPO on whom we had complete information on HRT use. Postoperative follow-up was 3.6 years.

The decision about prophylactic oophorectomy is difficult for many premenopausal women with BRCA1/2 mutations because of concerns and controversy about the use of hormone replacement therapy (HRT) after oophorectomy.

PATIENTS AND METHODS:A Markov decision analytic model used the most current epidemiologic data to assess the expected outcomes of prophylactic oophorectomy with or without HRT (to age 50 years or for life) in cohorts of women with BRCA1/2 mutations. Sensitivity analyses were conducted to assess the impact of alternative assumptions about effects of HRT, effects of prophylactic oophorectomy, and risks of cancer associated with BRCA1/2 mutations.

RESULTS:In our model, prophylactic oophorectomy lengthened life expectancy in women with BRCA1/2 mutations, irrespective of whether HRT was used after oophorectomy. This gain ranged from 3.34 to 4.65 years, depending on age at oophorectomy.

Use of HRT after oophorectomy was associated with relatively small changes in life expectancy (+0.17 to -0.34 years) when HRT was stopped at age 50, but larger decrements in life expectancy if HRT was continued for life (-0.79 to -1.09 years). HRT was associated with a gain in life expectancy of between 0.39 and 0.79 years for mutation carriers undergoing both prophylactic mastectomy and oophorectomy.

CONCLUSION:On the basis of the results of this decision analysis, we recommend that women with BRCA1/2 mutations undergo prophylactic oophorectomy after completion of childbearing, decide about short-term HRT after oophorectomy based largely on quality-of-life issues rather than life expectancy, and, if using HRT, consider discontinuing treatment at the time of expected natural menopause, approximately age 50 years.

a more recent meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group of 12 properly designed randomized trials found significantly greater disease-free and overall survival rates for women under the age of 50, regardless of nodal status, receiving ovarian ablation as a single adjuvant therapy.

Ovarian ablation was the original systemic therapy for breast cancer and has been in use for more than a hundred years, producing responses in approximately 30% of unselected women with metastatic breast cancer [1, 2], and in as many as 80% of women with steroid hormone receptor-positive (HR+) breast cancer [3, 4].

More recently, luteinizing hormone releasing hormone (LHRH) analogues, which act on the hypothalamic-pituitary-ovarian axis to suppress circulating estrogens to postmenopausal levels, have largely supplanted surgical and radiation-based approaches because of less morbidity and a lower likelihood of permanent amenorrhea, with the potential for restoration of fertility. Trials of adjuvant ovarian suppression have generally used either 2 [23] or 3 [26] years of treatment with an LHRH analogue, which produces comparable, and possibly even superior, outcomes to those obtained with CMF polychemotherapy in premenopausal HR+ patients. Ovarian ablation has long been established as an effective therapy for premenopausal women with metastatic breast cancer, with response rates ranging from 14%–70% in various studies [27].

Both the presence and degree of HR expression are strongly predictive of response to hormonal manipulation, with responses seen in approximately 60% of women having both ER+ and progesterone-receptor positive (PgR+) tumors, versus 30% in patients with either ER+ or PgR+ status alone [28].Fewer than 10% of women with receptor negative (ER−/PgR−) disease respond to endocrine therapies [29].

Following the introduction of goserelin, a number of phase II trials of the monthly injections were conducted in premenopausal and perimenopausal women with advanced breast cancer. A meta-analysis of these trials containing more than 200 evaluable patients reported a median survival of 26.5 months, an overall response rate of 36% (44% in ER+ patients), and a median duration of response of 44 weeks [33, 34], which were comparable to the outcomes historically obtained with oophorectomy in similar patient populations. the combination of an LHRH analogue and tamoxifen may be superior to endocrine monotherapy in premenopausal HR+ women with advanced breast cancer and can be considered for first-line therapy. Approximately 25% of breast cancer patients are premenopausal at the time of diagnosis [41]; of these, 60% have HR+ tumors [42]. These women are regarded as potentially appropriate for hormonal manipulation.

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the EBCTCG meta-analysis [10]. This overview of 12 randomized controlled trials enrolling a total of 2,102 patients reported that women under the age of 50 with early invasive breast cancer who underwent oophorectomy or ovarian irradiation, experienced approximately a 25% relative reduction in the risks of recurrence and mortality at 15 years of follow-up compared with those receiving no adjuvant therapy.

In summary, virtually all premenopausal women with early-stage HR+ breast cancer should receive adjuvant endocrine therapy. Combined endocrine therapy appears to be at least as effective as adjuvant CMF chemotherapy in this population.

Among women with early breast cancer, the effects of ovarian ablation on recurrence and death have been assessed by several randomised trials that now have long follow-up. In this report, the Early Breast Cancer Trialists’ Collaborative Group present their third 5-yearly systematic overview (meta-analysis), now with 15 years’ follow-up.

METHODS:In 1995, information was sought on each patient in any randomised trial of ovarian ablation or suppression versus control that began before 1990. Data were obtained for 12 of the 13 studies that assessed ovarian ablation by irradiation or surgery, all of which began before 1980, but not for the four studies that assessed ovarian suppression by drugs, all of which began after 1985. Menopausal status was not consistently defined across trials; therefore, the main analyses are limited to women aged under 50 (rather than “premenopausal”) when randomised. Oestrogen receptors were measured only in the trials of ablation plus cytotoxic chemotherapy versus the same chemotherapy alone.

The numbers of events were too small for any subgroup analyses to be reliable. The benefit was, however, significant both for those with (“node positive”) and for those without (“node negative”) axillary spread when diagnosed. In the trials of ablation plus cytotoxic chemotherapy versus the same chemotherapy alone, the benefit appeared smaller (even for women with oestrogen receptors detected on the primary tumour) than in the trials of ablation in the absence of chemotherapy (where the observed survival improvements were about six per 100 node-negative women and 12 per 100 node-positive women).

Among 1354 women aged 50 or over when randomised, most of whom would have been perimenopausal or postmenopausal, there was only a nonsignificant improvement in survival and recurrence-free survival.

INTERPRETATION:In women aged under 50 with early breast cancer, ablation of functioning ovaries significantly improves long-term survival, at least in the absence of chemotherapy. Further randomised evidence is needed on the additional effects of ovarian ablation in the presence of other adjuvant treatments, and to assess the relevance of hormone-receptor measurements.

To evaluate institutional experiences regarding laparoscopic salpingo-oophorectomy in breast cancer patients and to compare the technique with gonadotropin-releasing hormone (GnRH) analogs among premenopausal women with hormone-sensitive breast cancer.
METHODS:Between 2004 and 2009, 103 women with breast cancer underwent laparoscopic salpingo-oophorectomy at Addenbrooke’s Hospital, Cambridge, UK. All relevant medical records-including reasons for salpingo-oophorectomy, peri-operative events, and subsequent follow-up-were reviewed.
RESULTS:In the study period, 3 (2.9%) women experienced a recurrence of breast cancer but none had primary peritoneal/ovarian cancer within a median follow-up interval of 34 months (range, 0-70 months). No operative complications were noted among these women and all of them went home on the day of their operation.
CONCLUSION:Laparoscopic salpingo-oophorectomy seems to be a safe, permanent, and cost-effective method of ovarian ablation compared with the use of GnRH analogs. Salpingo-oophorectomy also considerably reduces the risk of subsequent ovarian/fallopian tube malignancy in this high-risk population.

2007

32) www.ncbi.nlm.nih.gov/pubmed/17713096
Eur J Gynaecol Oncol. 2007;28(4):294-6.
Laparoscopic oophorectomy either with or without hysterectomy for early breast cancer. Kucera E, Holub Z, Svobodova G. Department of Obstetrics and Gynecology, Institute of Care for Mother and Child, Prague, Czech Republic. The aim of this study was to assess the surgical results, complications and pathological findings of laparoscopic ovarian ablation either with or without hysterectomy in women with early-stage breast cancer (BC).

METHODS:Ninety women in early breast cancer stage who underwent laparoscopic bilateral salpingo-oophorectomy (BSO) either with or without hysterectomy were identified in a retrospective study conducted between January 2000 and December 2006. Tamoxifen antiestrogen therapy was used prior to hysterectomy.

RESULTS:Forty-eight consecutive patients underwent laparoscopic hysterectomy with bilateral salpingo-oophorectomy and 42 with ovarian ablation only. The mean operative time for the laparoscopic hysterectomy and bilateral salpingo-oophorectomy or BSO alone was 82 min and 47.8 min, respectively. Blood loss was minimal in both groups (range: 20-250 ml). The rate of postoperative complications was very low (4.4%). One of all ovaries removed by laparoscopy showed ovarian breast carcinoma metastasis. Histopathologic examination revealed concomitant findings of leiomyoma, adenomyosis or endometrial abnormalities in 64.5% of hysterectomy specimens.

CONCLUSION:Our experience with ovarian ablation either with or without hysterectomy confirmed that the use of a minimally invasive technique is feasible. We assume that ovarian ablation and hysterectomy is an appropriate treatment for premenopausal women at risk (BRCA positive) or for patients with concomitant benign uterine pathology, treated with tamoxifen in first-line therapy. Removing the uterus allows women to take only estrogens rather than combination HRT. Further investigation into the indications of disease where laparoscopic ablative surgery is appropriate in the management of early breast cancer is needed.

Ovarian ablation is an effective treatment for premenopausal women with hormone receptor positive breast cancer. It can be achieved permanently by surgery or radiotherapy and reversibly by LhRH agonists. This paper discusses the evidence that it is an effective adjuvant therapy and defines the place of oophorectomy in the management of such patients. The achievement of an amenhorreic state is important and chemotherapy may well exert some of its effects by causing ovarian suppression. The use of LhRH agonists in managing such patients is discussed.

Aromatase inhibitors have become well established for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer and for adjuvant hormonal therapy for primary breast cancer. Benefit of aromatase inhibition has not yet been extended to premenopausal women. Ovarian ablation by oophorectomy, ovarian radiation or hormonal suppression is the initial recommended treatment for hormone receptor-positive metastatic breast cancer in premenopausal women. The addition of tamoxifen improves the benefit of ovarian ablation/ovarian suppression. Addition of aromatase inhibitors to luteinizing hormone-releasing hormone analogs has been reported to significantly decrease circulating estrogens and produce tumor responses in only a very small number of patients over the last 15 years. We treated three premenopausal patients with hormone receptor-positive metastatic breast cancer with combined oophorectomy or ovarian irradiation and anastrozole. One patient remained free of progression for 4 years, while the other two remained free of progression for more than 5 and 3 years, respectively. We also note that monthly zoledronic acid for 4 years produced sclerosis of vertebral body metastasis. We conclude that combined ovarian ablation and aromatase inhibition is a feasible treatment modality that deserves more attention and further investigation for hormone receptor-positive metastatic breast cancer in premenopausal women.

Percutaneous progesterone topically applied on the breast has been proposed and widely used in the relief of mastalgia and benign breast disease by numerous gynecologists and general practitioners. However, its chronic use has never been evaluated in relation to breast cancer risk. The association between percutaneous progesterone use and the risk of breast cancer was evaluated in a cohort study of 1150 premenopausal French women with benign breast disease diagnosed in two breast clinics between 1976 and 1979. The follow-up accumulated 12,462 person-years. Percutaneous progesterone had been prescribed to 58% of the women.

There was no association between breast cancer risk and the use of percutaneous progesterone (RR = 0.8; 95% confidence interval 0.4-1.6). Although the combined treatment of oral progestogens with percutaneous progesterone significantly decreased the risk of breast cancer (RR = 0.5; 95% confidence interval 0.2-0.9) as compared with nonusers, there was no significant difference in the risk of breast cancer in percutaneous progesterone users versus nonusers among oral progestogen users. Taken together, these results suggest at least an absence of deleterious effects caused by percutaneous progesterone use in women with benign breast disease.

1997 – Women with family history of breast cancer –
Reduced Mortality for HRT users

36) www.ncbi.nlm.nih.gov/pubmed/9412302 Ann Intern Med. 1997 Dec 1;127(11):973-80.
The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer.Sellers TA, Mink PJ, Cerhan JR, Zheng W, Anderson KE, Kushi LH, Folsom AR.Division of Epidemiology, University of Minnesota, Minneapolis 55454, USA.

The risks and benefits of hormone replacement therapy (HRT) are of considerable interest and importance, especially in terms of whether they differ among subsets of women.

OBJECTIVE: To determine whether HRT is associated with increased risks for breast cancer and total mortality in women with a family history of breast cancer.
DESIGN: Prospective cohort study.

MEASUREMENTS: Incidence rates of and relative risks for breast cancer (n = 1085) and total mortality (n = 2035) through 8 years of follow-up were calculated by using data from the State Health Registry of Iowa and the National Death Index.

RESULTS: A family history of breast cancer was reported by 12.2% of the cohort at risk. Among women with a family history of breast cancer, those who currently used HRT and had done so for at least 5 years developed breast cancer at an age-adjusted annual rate of 61 cases per 10,000 person-years (95% CI, 28 to 94 cases); this rate was not statistically significantly higher than the rate in women who had never used HRT (46 cases per 10,000 person-years [CI, 36 to 55 cases]).

Among women with a family history, those who used HRT had a significantly lower risk for total mortality than did women who had never used HRT (relative risk, 0.67 [CI, 0.51 to 0.89]), including total cancer-related mortality (relative risk, 0.75 [CI, 0.50 to 1.12]).

The age-adjusted annual mortality rate for women using HRT for at least 5 years was 46 deaths per 10,000 person-years (CI, 19 to 74 deaths); this is roughly half the rate seen in women who had never used HRT (80 deaths per 10,000 person-years [CI, 69 to 92 deaths]).

CONCLUSIONS: These data suggest that HRT use in women with a family history of breast cancer is not associated with a significantly increased incidence of breast cancer but is associated with a significantly reduced total mortality rate.

This review was designed to determine from the best evidence whether there is an association between postmenopausal hormonal treatment and breast cancer risk. Also, if there is an association, does it vary according to duration and cessation of use, type of regimen, type of hormonal product or route of administration; whether there is a differential effect on risk of lobular and ductal cancer; and whether hormone treatment is associated with breast cancers that have better prognostic factors?

Data sources for the review included Medline, the Cochrane Database of Systematic Reviews (Cochrane Library, 2005) and reference lists in the identified citations. Eligible citations addressed invasive breast cancer risk among postmenopausal women and involved use of the estrogen products with or without progestin that are used as treatment for menopausal symptoms. Abstracted data were demographic groupings, categories of hormone use, categories of breast cancer, two-by-two tables of exposure and outcome and adjusted odds ratios, relative risks (RRs) or hazard rates. Average estimates of risk were weighted by the inverse variance method, or if heterogeneous, using a random effects model.

The average breast cancer risk with estrogen-progestin use was 1.24 (95% CI = 1.03-1.50) in four randomized trials involving 19 756 women.

The average risks reported in recent epidemiological studies were higher: 1.18 (95% CI = 1.01-1.38) with current use of estrogen alone and 1.70 (95% CI = 1.36-2.17) with current use of estrogen-progestin. The association of breast cancer with current use was stronger than the association with ever use, which includes past use. For past use, the increased breast cancer risk diminished soon after discontinuing hormones and normalized within 5 years. Reasonably adequate data do not show that breast cancer risk varies significantly with different types of estrogen or progestin preparations, lower dosages or different routes of administration, although there is a small difference between sequential and continuous progestin regimens.

Epidemiological studies indicate that estrogen-progestin use increases risk of lobular more than ductal breast cancer, but the number of studies and cases of lobular cancer remains limited.

Among important prognostic factors, the stage and grade in breast cancers associated with hormone use [corrected] do not differ significantly from those in non-users, but breast cancers in estrogen-progestin users are significantly more likely to be estrogen receptor (ER) positive.

In conclusion, valid evidence from randomized controlled trials (RCTs) indicates that breast cancer risk is increased with estrogen-progestin use more than with estrogen alone.

Epidemiological evidence involving more than 1.5 million women agrees broadly with the trial findings. Although new studies are unlikely to alter the key findings about overall breast cancer risk, research is needed, however, to determine the role of progestin, evaluate the risk of lobular cancer and delineate effects of hormone use on receptor presence, prognosis and mortality in breast cancer.

Menopausal hormone therapy (HT) is typically withheld from breast cancer survivors because of concerns about risk for recurrence. Our objectives were to estimate the effects of HT on recurrence in breast cancer survivors and to examine the reliability of these estimates.
Methods

In a systematic review of the literature we identified all reports of HT use in breast cancer survivors that included comparison groups. Study design features that might affect selection of participants, detection of recurrence, and manuscript publication were assessed. The relative risks for breast cancer recurrence associated with HT were combined with random effects models.
Results

Conclusion: Results from observational studies of HT conducted in breast cancer survivors are discrepant with results from randomized trials. Observational studies of HT use in breast cancer survivors have design limitations that cannot be controlled for using standard statistical methods. Therefore, the randomized clinical trial data provide the only reliable estimates of the effect of HT use on recurrence risks in breast cancer survivors.
——————————–2006 BATUR – Cleveland Clinic – Review of ALL studies-
HRT users had decreased recurrence and decreased mortality

To assess the effect of menopausal hormone therapy (HT) on reoccurrence, cancer-related mortality, and overall mortality after a diagnosis of breast cancer.

METHODS:We performed a quantitative review of all studies reporting experience with menopausal HT for symptomatic use after a diagnosis of breast cancer. Rates of reoccurrence, cancer-related mortality, and overall mortality were calculated in this entire group. A subgroup analysis was performed in studies using a control population to assess the odds ratio of cancer reoccurrence and mortality in hormone users versus non-users.

RESULTS: Fifteen studies encompassing 1416 breast cancer survivors using HT were identified. Seven studies included a control group comprised of 1998 patients.

“Compared to non-users, patients using HT had a decreased chance of reoccurrence and cancer-related mortality with combined odds ratio of 0.5 (95% CI: 0.2-0.7) and 0.3 (95% CI: 0.0-0.6), respectively.”

CONCLUSIONS:

In our review, menopausal HT use in breast cancer survivors was not associated with increased cancer reoccurrence, cancer-related mortality or total mortality. Despite conflicting opinions on this issue, it is important for primary care physicians to feel comfortable medically managing the increasing number of breast cancer survivors. In the subset of women with severe menopausal symptoms, HT options should be reviewed if non-hormonal methods are ineffective. Future trials should focus on better ways to identify breast cancer survivors who may safely benefit from HT versus those who have a substantial risk of reoccurrence with HT use.
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Our commentary in the July 2009 issue of ONCOLOGY concluded that the current level of evidence for safety and efficacy of “natural” hormone replacement therapy (NHRT) is not conclusive. In terms of safety, the majority of data suggests that NHRTs demonstrate risks similar to those of conventional hormone replacement therapy (HRT). Efficacy trials of NHRTs have produced mixed and sometimes contradictory results. We further suggested that the administration of hormone therapy rely on evidence-based clinical judgment; NHRT advice to women should be based on the same risk/benefit assessment that would be used when considering conventional HRT.

Drs. Creasman and DiSaia use this as a segue in their Letter to the Editor to defend the use of HRT for women, taking the position that there is really a lot of fuss about nothing with HRT, and if NHRT is the same, no problem. They argue that for breast cancer survivors, “In view of the present data, we feel it is important for women to know there are choices, and current data would suggest that there is no increased risk of recurrence with HRT.”

Their first defense of HRT is a 2002 citation by Chlebowski et al,[1] but the writers fail to mention the fact that these authors concluded,

“Relatively short-term combined estrogen plus progestin use increases incident breast cancers, which are diagnosed at a more advanced stage compared with placebo use, and also substantially increases the percentage of women with abnormal mammograms. These results suggest estrogen plus progestin may stimulate breast cancer growth and hinder breast cancer diagnosis.”

They go on to cite other studies including a small (n = 43) 1985 trial by Matelski et al.[2] The writers conclude from this citation that “In the 1970s and early 1980s, several prospective randomized studies compared estrogen with tamoxifen(Drug information on tamoxifen) in such women. The results were similar.” Their conclusion is not shared by the evidence. Even the authors of their citation disagree, concluding that “Initial hormonal therapy with tamoxifen in postmenopausal patients with advanced breast cancer and ERP status positive or unknown is superior to primary estrogen treatment.”

The writers also comment on the HABITS trial,[3] which was stopped as a result of increased breast cancer risk in the HRT arm and the Stockholm trial.[4] They conclude “In view of the present data, we feel it is important for women to know there are choices, and current data would suggest that there is no increased risk of recurrence with HRT.” Once again, their conclusions are not consistent with the evidence or other well considered analyses.

Further Evidence

Prentice et al[5] examined the effects of daily 0.625-mg conjugated equine estrogens (Drug information on estrogens) plus 2.5-mg medroxyprogesterone (Drug information on medroxyprogesterone) acetate in relation to both prior hormone therapy and time from menopause to first use of postmenopausal hormone therapy (“gap time”) in the Women’s Health Initiative (WHI) trial and in a corresponding subset of the WHI observational study on postmenopausal women with a uterus enrolled at 40 US clinical centers during 1993–1998. The authors found that hazard ratios agreed between the two cohorts at a specified gap time and time from hormone therapy.

They determined that the “Combined trial and observational study data support an adverse effect on breast cancer risk.” They further concluded, “The WHI clinical trial and observational study each support an adverse effect of daily 0.625-mg conjugated equine estrogen plus 2.5-mg medroxyprogesterone acetate on breast cancer. Women who initiate treatment soon after menopause and continue for many years appear to be at particularly high risk.” As if this weren’t enough, a recent review by Chlebowski et al[6] showed a significant increase in deaths (not incidence) from lung cancer for women receiving estrogen plus progestin compared to placebo controls enrolled in the WHI.

Conclusion

The writers’ argument in favor of the safety of HRT is not supported by the evidence, including their own references. Our conclusions in the July 2009 ONCOLOGY Commentary remain unchanged—namely that HRT (including NHRT) should be based on a balanced risk/benefit assessment and that high-risk patients including survivors of hormone-driven breast cancer are not appropriate candidates for HRT. As new clinical trials increase our body of knowledge, we will hopefully have more tools and flexibility when making clinical judgments, but at this time we must not lose sight of the principle of “do no harm.”

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2009 creaseman and desaia

www.cancernetwork.com/display/article/10165/1486356
Hormone Replacement and Breast Cancer Risk:
Reconsidering the Data By William T. Creasman, MD Department of Obstetrics and Gynecology Medical University of South Carolina Charleston, South Carolina ­ Philip J. DiSaia, MD Department of Obstetrics and Gynecology University of California, Irvine Irvine, California | November 12, 2009

In many instances, women are told that HRT is absolutely contraindicated, yet we are unaware of any clinical data to substantiate that statement. In view of the present data, we feel it is important for women to know there are choices, and current data would suggest that there is no increased risk of recurrence with HRT.

There is evidence that hormone replacement therapy (HRT) may both stimulate and inhibit breast cancers, giving rise to a spectrum of activities, which are frequently hard to understand. Here we summarise the evidence for these paradoxical effects and, given the current data, attempt to give an indication where it may or may not be appropriate to prescribe HRT.It is clear that administration of oestrogen-progestin (E-P) and oestrogen alone (E) HRT is sufficient to stimulate the growth of overt breast tumours in women since withdrawal of HRT results in reduction of proliferation of primary tumours and withdrawal responses in metastatic tumours. E-P, E including tibolone are associated with increased local and distant relapse when given after surgery for breast cancer. For women given HRT who do not have breast cancer the only large randomised trial (WHI) of E-P or E versus placebo has produced some expected and also paradoxical results. E-P increases breast cancer risk as previously shown in observational studies. Risk is increased, particularly in women known to be compliant. Conversely, E either has no effect or reduces breast cancer risk consistent with some but not all observational studies.

Two observational studies report a decrease or at least no increase in risk when E-P or E are given after oophorectomy in young women with BRCA1/2 mutations. Early oophorectomy increases death rates from cardiovascular and other conditions and there is evidence that this may be reversed by the use of E post-oophorectomy. HRT may thus reduce the risk of breast cancer and other diseases (e.g., cardiovascular) in young women and increase or decrease them in older women.

The use of hormone therapy for climacteric symptoms in patients with breast cancer has become a significant and important point of discussion due in part to the improved survival from this disease in recent years. “There is a theoretic risk that exogenous hormones will stimulate the growth of microscopic disease and lead to decreased survival and increased recurrence.” In addition, 2 large studies have shown that there is an association between hormone therapy and breast cancer risk in women without an earlier history of breast cancer. Other studies suggest that estrogen alone may have a superior safety profile than estrogen and progesterone in combination.

“Hormone therapy could be justified for improvement of quality of life when other options have failed and the patient is informed of the risks.”

The LIBERATE randomised trial(over3000women
randomised) showedanincreasedriskofrecurrenceinwomentak-
ing tibolonevsplaceboforvasomotorsymptoms [73].
Based on these studies,systemic HRT is not recommended in breastcancer survivors. The use of vaginal oestrogens is discussedbelow.

The importance of addressing survivorship issues has been emphasised in recent years. As cancer therapies improve there is a growing population of cancer survivors, which includes many women with premature menopause. Women who are premenopausal at the time of their cancer diagnosis may have specific survivorship issues to be addressed, including infertility, early menopause and sexual dysfunction. These factors can continue have a significant impact on the quality of life of these patients at long term follow up. Data for this Review were identified by searches of MEDLINE, PubMed, and references from relevant articles using the search terms ‘HRT’, ‘women/female cancer/tumour’, ‘menopause’ and ‘survivorship’. Abstracts and reports from meetings were excluded. Only papers published in English between 1980 and 2010 were included.

The aims of this review are to:
• Address the hormonal factors which impact on cancer survivorship for premenopausal women
• Review the debate for the role of hormone replacement therapy (HRT) in cancer survivors
• Provide information for physicians and patients regarding the management of hormonally driven survivorship issues (for different tumour types), based on current evidence

The recommendations for practice are that HRT may be offered for the alleviation of vasomotor symptoms in cancer survivors who undergo premature menopause up to the age of natural menopause (51 years in the UK). “HRT (including vaginal oestrogen preparations) is contraindicated in survivors of oestrogen receptor positive breast cancer and low grade endometrial leiomyosarcoma,where non-HRT alternatives should be considered to alleviate symptoms.”

Exogenous estrogen (administered as HRT) reduces breast cancer rates.
HRT based on estrogen alone helps manage menopausal symptoms.
More data are needed to elaborate on estrogen’s role in chemoprevention.

SAN ANTONIO – While endogenous estrogen (i.e., estrogen produced by ovaries and by other tissues) does have a well-known carcinogenic impact, hormone replacement therapy (HRT) utilizing estrogen alone (the exogenous estrogen) provides a protective effect in reducing breast cancer risk, according to study results presented at the 33rd Annual CTRC-AACR San Antonio Breast Cancer Symposium, held Dec. 8-12.

“Our analysis suggests that, contrary to previous thinking, there is substantial value in bringing HRT with estrogen alone to the guidelines. The data show that for selected women it is not only safe, but potentially beneficial for breast cancer, as well as for many other aspects of women’s health,” said lead researcher Joseph Ragaz, M.D., medical oncologist and clinical professor in the faculty of medicine, School of Population and Public Health at The University of British Columbia, Vancouver, BC, Canada.

Hormone replacement therapy (HT) is known to increase the risk of breast cancer in healthy women, but its effect on breast cancer risk in breast cancer survivors is less clear. The randomized HABITS study, which compared HT for menopausal symptoms with best management without hormones among women with previously treated breast cancer, was stopped early due to suspicions of an increased risk of new breast cancer events following HT. We present results after extended follow-up.

METHODS: HABITS was a randomized, non-placebo-controlled noninferiority trial that aimed to be at a power of 80% to detect a 36% increase in the hazard ratio (HR) for a new breast cancer event following HT. Cox models were used to estimate relative risks of a breast cancer event, the maximum likelihood method was used to calculate 95% confidence intervals (CIs), and chi(2) tests were used to assess statistical significance, with all P values based on two-sided tests. The absolute risk of a new breast cancer event was estimated with the cumulative incidence function. Most patients who received HT were prescribed continuous combined or sequential estradiol hemihydrate and norethisterone.

RESULTS:

Of the 447 women randomly assigned, 442 could be followed for a median of 4 years. Thirty-nine of the 221 women in the HT arm and 17 of the 221 women in the control arm experienced a new breast cancer event (HR = 2.4, 95% CI = 1.3 to 4.2). Cumulative incidences at 5 years were 22.2% in the HT arm and 8.0% in the control arm. By the end of follow-up, six women in the HT arm had died of breast cancer and six were alive with distant metastases. In the control arm, five women had died of breast cancer and four had metastatic breast cancer (P = .51, log-rank test).

CONCLUSION:

After extended follow-up, there was a clinically and statistically significant increased risk of a new breast cancer event in survivors who took HT.

METHODS: We systematically searched studies reporting the use of HT in BC patients. We selected 20 studies in which we evaluated the methodology, characteristics of the studied populations and outcomes in terms of mortality and recurrence rates (RRs).

RESULTS:Many studies evaluating HT were uncontrolled and retrospective. Ten prospective and two randomized studies were found. These were characterized by heterogeneity in populations, tumour characteristics, prognostic factors and treatments. Two studies reported a reduced RR, and two reported lowered BC mortality rates in HT users. One randomized study reported an increased rate of new BC events in HT users.

CONCLUSIONS: There are currently no reassuring data indicating the absence of a harmful effect of HT. Further studies should analyse whether some regimens are safer than others. There is a need for randomized trials assessing the safety of these regimens. In the meantime, patients should be informed about the absence of safety data.

OBJECTIVE: Substitution of estrogens (hormone replacement therapy [HRT]) is the most common therapy and prophylaxis of postmenopausal complaints. However, in most studies, long-term HRT has been associated with an increased risk for breast cancer, but the influence on a prognosis of breast cancer has been examined rarely.

STUDY DESIGN: For further investigation, we analyzed 1072 patients aged 45-70 years at the time of first diagnosis of breast cancer with and without preoperative HRT with regard to the incidence of distant metastases and overall survival. Of these, 279 women were premenopausal (mean, 47.8 +/- 3.2 years); 793 women were postmenopausal (mean, 54.5 +/- 3.5 years);

320 women had received HRT over a minimum of 1 year (mean, 5.5 +/- 4.0 years; group HRT+); and 473 women had not received HRT (group HRT-). The median follow-up time was 73.2 months.

RESULTS: Although body mass index, tumor size, and grading of group HRT were significantly higher than in group HRT+, nodal status, S-phase fraction, hormone-receptor status, and local recurrence showed no significant differences.

In regard to the incidence of distant metastases, women without HRT have significantly (P < .001) more metastases to bone (68 vs 20 women), lung (47:13 women), and liver (47:13 women). Overall survival was significantly lower in the HRT- group.

CONCLUSION: We were able to show that the use of HRT before the diagnosis of
breast cancer results in more favorable primary tumors, with a lower incidence of recurrences and a better overall survival rate. This might be due to normalized bone metabolism by the use of HRT, which may lower the conditions of tumor cell seeding.

There is not only a need for scientific data regarding the risk of recurrence of breast cancer by starting hormone replacement therapy (HRT) but also regarding the patients’ needs for HRT.

OBJECTIVES:To examine the severity of climacteric complaints in breast cancer patients and to examine if they are willing to take HRT.

METHODS:In November 2003, a questionnaire was sent to 469 breast cancer survivors. The survey examined on a scale base the severity of climacteric complaints and the patient’s opinion on starting HRT.

RESULTS:More than 76% of the patients complained that they experience or had experienced hot flushes or night sweating. More than half (53%) of this group found the inconvenience severe to extreme, affecting the patient’s quality of life. A majority (80.5%) patients who had already taken HRT, found that it improved their quality of life substantially. When the results of observational studies were explained regarding HRT in breast cancer survivors, a majority said they would take or would consider taking HRT (57.9%).

CONCLUSION:While physicians are more reserved in prescribing HRT in breast cancer survivors, a combination of severe symptomatic climacteric complaints and the willingness of the patient to be treated should at least result in a “consideration” of prescribing HRT.

The Israeli Society for Clinical Oncology and Radiotherapy appointed experts in breast cancer therapy to assess the Society’s policy regarding hormone replacement therapy (HRT) in breast cancer survivors with menopausal symptoms. The first policy letter was published in November 2002, and referred to available literature at that time which included retrospective data alone.

The professional literature suggested no increased risk in breast cancer recurrence or cancer specific mortality, and no effect on overall survival with the use of HRT for a limited period (up to 3 years).

This data served as the rationale for international prospective studies. Former committee recommendations and precautions are detailed in the original publication. In February 2004, the interim analysis of a prospective trial, the HABIT (Hormonal replacement therapy after breast cancer–is it safe?) was published. In that trial, breast cancer survivors with menopausal symptoms were randomized to HRT (estrogens with or without progestins) or no therapy for 2 years. A total of 434 women were recruited from centers in Scandinavia who participated with the International Breast Cancer and the European Organization for Research and Treatment groups.

Analysis was restricted to 345 women with at least one follow up report; median follow-up period was 2.1 years. The relative risk for breast cancer event was 3.5 (95% C.I. 1.5-8.1) in HRT users as compared with the non-HRT group and the HABIT trial was terminated. Study limitations are discussed.

Thereby, at this time HRT can no longer be considered safe in breast cancer survivors. Physicians treating breast cancer survivors for severe menopausal symptoms should present study results and alternative non-hormonal treatment options to allow patients optimized consented treatment decisions.

This guideline has been reviewed by the Breast Disease Committee and approved by
the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada.

CONCLUSIONS
The opinion that estrogens and estrogen treatment are deleterious for breast cancer needs to be refocused. Knowing the current data, a proper risk-benefit assessment of HRT use in women with risk factors for breast cancer or in women diagnosed with a breast cancer needs to be presented. We need to wait for the prospective,
randomized clinical trials that are presently ongoing to have a
definitive conclusion.

RECOMMENDATIONS

1. HRT after treatment of breast cancer has not been demonstrated to have an adverse impact on recurrence and mortality. (II-2

OBJECTIVES: After recalling the classical contra-indication of hormone replacement therapy (HRT) concerning patients with a personal history of breast cancer (BC), and arguments that may be opposed, the authors report the present results of a prospective study undertaken in the Center of Breast Diseases in Saint-Louis hospital in Paris since February 1992.

PATIENTS AND METHODS: By April 2001, 230 patients had been included. A free interval of 2 years at least since the treatment of the primary BC has been observed. The reasons for prescribing HRT were vasomotor troubles (flushes, nightly sweats) or a dyspareunia, which were severe and not controlled by non-hormonal treatments. There was also an indication of a major osteoporotic or cardiovascular danger. In fact, many of these patients had a premature, artificial, chemo-induced menopause. The HRT most often used was an estro-progestin association (estradiol + a progestin compound) given either continuously or with a 5-d interruption each month. The mean duration of treatment was 2.5 years.

RESULTS: Results, concerning the improvement of menopause troubles, were remarkable in the great majority of troubles. HRT had to be stopped in 39 cases, reading as follows: 17 cases for relapses (seven local, six in the contro-lateral breast and four metastases (7%)). Also, 22 patients (9%) interrupted their HRT for serious side-effects. A case-control study did not show any significant difference between with and without HRT patients concerning the overall survival without relapse.

DISCUSSION AND CONCLUSIONS: Quality of life of patients was often substantially improved, and a deleterious effect on the cancer disease was not found. Our results are in agreement with the literature from other countries. However, one must be cautious. In such circumstances, HRT must be prescribed with the informed consent of the patients and delivered in appropriate hospital and university centers. It is wished that large randomised prospective studies may be undertaken.

The role of hormone replacement therapy in women with a previous diagnosis of breast cancer.
Kathleen I. Pritchard, Humaira Khan, Mark Levine, and The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer

To provide information and recommendations to women with a previous diagnosis of breast cancer and their physicians regarding hormone replacement therapy (HRT).
Outcomes

Control of menopausal symptoms, quality of life, prevention of osteoporosis, prevention of cardiovascular disease, risk of recurrence of breast cancer, risk of death from breast cancer.
Evidence

Systematic review of English-language literature published from January 1990 to July 2001 retrieved from MEDLINE and CANCERLIT.

Recommendations

Routine use of HRT (either estrogen alone or estrogen plus progesterone) is not recommended for women who have had breast cancer.

Randomized controlled trials are required to guide recommendations for this group of women. Women who have had breast cancer are at risk of recurrence and contralateral breast cancer. The potential effect of HRT on these outcomes in women with breast cancer has not been determined in methodologically sound studies.

However, in animal and in vitro studies, the development and growth of breast cancer is known to be estrogen dependent. Given the demonstrated increased risk of breast cancer associated with HRT in women without a diagnosis of breast cancer, it is possible that the risk of recurrence and contralateral breast cancer associated with HRT in women with breast cancer could be of a similar magnitude. ·

Postmenopausal women with a previous diagnosis of breast cancer who request HRT should be encouraged to consider alternatives to HRT.

If menopausal symptoms are particularly troublesome and do not respond to alternative approaches, a well-informed woman may choose to use HRT to control these symptoms after discussing the risks with her physician. In these circumstances, both the dose and the duration of treatment should be minimized.

theoncologist.alphamedpress.org/content/6/4/353.fullOncologist. 2001;6(4):353-62.
Hormone replacement in women with a history of breast cancer.Pritchard KI.Toronto-Sunnybrook Regional Cancer Centre and The University of Toronto, Toronto, Ontario, Canada. kathy.pritchard@tsrcc.on.ca

Hormone replacement therapy (HRT) is typically avoided for women with a history of breast cancer because of concerns that estrogen will stimulate recurrence. In this study, we sought to evaluate the impact of HRT on recurrence and mortality after a diagnosis of breast cancer.
METHODS:

Data were assembled from 2755 women aged 35-74 years who were diagnosed with incident invasive breast cancer while they were enrolled in a large health maintenance organization from 1977 through 1994. Pharmacy data identified 174 users of HRT after diagnosis. Each HRT user was matched to four randomly selected nonusers of HRT with similar age, disease stage, and year of diagnosis. Women in the analysis were recurrence free at HRT initiation or the equivalent time since diagnosis. Rates of recurrence and death through 1996 were calculated. Adjusted relative risks were estimated by use of the Cox regression model. All statistical tests were two-sided.
RESULTS:

The rate of breast cancer recurrence was 17 per 1000 person-years in women who used HRT after diagnosis and 30 per 1000 person-years in nonusers
(adjusted relative risk for users compared with nonusers = 0.50; 95% confidence interval [CI] = 0.30 to 0.85).

The relatively low rates of recurrence and death were observed in women who used any type of HRT (oral only = 41% of HRT users; vaginal only = 43%; both oral and vaginal = 16%). No trend toward lower relative risks was observed with increased dose.
CONCLUSION: We observed lower risks of recurrence and mortality in women who used HRT after breast cancer diagnosis than in women who did not. Although residual confounding may exist, the results suggest that HRT after breast cancer has no adverse impact on recurrence and mortality.
Unopposed estrogens only – 50% less recurrence compared to never users. www.menopausemgmt.com/issues/10-04/News%20Briefs.pdf

HRT After Breast Cancer: Recurrence and Mortality Findings from a data analysis suggest that hormone replacement therapy (HRT) in women previously diagnosed with invasive breast cancer does not appear to increase the risk of recurrence or mortality, and might even have a protective effect.

PURPOSE: Hormone replacement therapy (HRT) is typically withheld from women with breast cancer because of concern that it might increase the risk of recurrence. The purpose of this study was to quantify the risk of recurrent breast cancer associated with HRT among breast cancer survivors. METHODS: We performed a systematic literature review through May 1999, calculating the relative risk (RR) of breast cancer recurrence in each study by comparing the number of recurrences in the HRT group to those in the control group. In studies that did not contain a control group, we constructed one by estimating the expected number of recurrences based on data from the Early Breast Cancer Trialists’ Collaborative
Group, adjusting for nodal status and disease-free interval. RRs across all studies were combined using random-effects models.

RESULTS: Of the 11 eligible studies, four had control groups and included 214 breast cancer survivors who began HRT after a mean disease-free interval of 52 months.

Over a mean follow-up of 30 months, 17 of 214 HRT users experienced recurrence (4.2% per year), compared with 66 of 623 controls (5.4% per year). HRT did not seem to affect breast cancer recurrence risk (RR = 0.64, 95% confidence interval [CI], 0.36 to 1.15). Including all 11 studies in the analyses (669 HRT users), using estimated control groups for the seven uncontrolled trials, the combined RR was 0.82 (95% CI, 0.58 to 1.15).

CONCLUSION: Although our analyses suggest that HRT has no significant effect on breast cancer recurrence, these findings were based on observational data subject to a variety of biases.

There has been lots of conflicting news about the relationship between hormone replacement therapy and breast cancer. The latest study to address this issue comes from the Journal of the National Cancer Institute (5/16/01). The study found that for women who have already had breast cancer, hormone replacement therapy did NOT increase their risk of breast cancer recurrence. In fact, the study found that HRT might even lower the chances of a breast cancer recurrence in those women and lower their risk of death from breast cancer if it does recur. In addition, this study showed that HRT use after a diagnosis of breast cancer reduced the relative risk of death from all causes.

Investigators at the University of Washington in Seattle evaluated data from 2,755 women, aged 35 to 74, who had been diagnosed with invasive breast cancer between 1977 and 1994. Of these women, there were 174 who elected to use hormone replacement therapy after their diagnosis. Each of those HRT users was matched to 4 randomly selected nonusers with similar age, disease stage, and year of diagnosis. After following these women for approximately 4 years, rates of breast cancer recurrence and death from all causes was calculated. The results show that the rate of breast cancer recurrence was 17 per 1000 person-years in women who used HRT after their diagnosis of breast cancer, and nearly twice as high (30 per 1000 person-years) in women who did not use HRT after their diagnosis. Breast cancer mortality rates were 5 per 1000 person-years in HRT users and three times higher (15 per 1000 person-years) in nonusers. Mortality rates from all causes were nearly twice as high in the women who did not use HRT (16 per 1000 person-years in HRT users versus 30 per 1000 person-years in nonusers).

What do these numbers mean in plain English? After following these women for nearly 4 years, investigators found that the rate of cancer recurrence in women who used HRT after having been diagnosed with invasive breast cancer was approximately HALF of what it was in nonusers after adjustment for confounding factors.

When they evaluated causes of death in these women, the researchers found that the risk of death from breast cancer was three times greater in the women who did NOT use HRT than in the women who did. When death from ALL causes was evaluated, the women who did not take HRT had TWICE the risk of death compared to the women who took HRT. The results did not vary based upon the length of time that the women took HRT or whether they used the vaginal or pill form of HRT.

The results of this study argue against any causal influence of HRT on breast cancer recurrence and mortality. It may also influence the recommendations that women are given about resuming HRT after breast cancer diagnosis.

“HRT use is associated with not only the risk of developing a new breast cancer (the end point used in most observational studies describing breast cancer ‘‘risk’’), but also the additional and more proximate risk of stimulating growth and clinical expression of pre-existing breast cancer metastatic foci.”

METHODS: Current information on HRT, breast cancer, and chronic disease prevention is reviewed in the context of risks faced by women with resected breast cancer.

RESULTS: Breast cancer patients, unwilling to trade symptom reduction for even a small increase in recurrence risk, are at substantially increased risk of death from breast cancer relative to other causes. Observational studies suggest that long-term HRT increases breast cancer development. The influence of HRT on the growth of established breast cancer has not been determined; however, estrogen reduction (oophorectomy) significantly reduces recurrence in premenopausal women, and current evidence cannot exclude a risk that HRT increases recurrence to the same degree. The following issues are of particular relevance to breast cancer survivors: HRT reduces mammographic sensitivity, increases thromboembolic events, and increases endometrial cancer risk. Although benefit for HRT is commonly inferred from observational studies, randomized trials of HRT on all-cause mortality have not been completed. For coronary heart disease prevention, an array of strategies independent of HRT are available, with some (tamoxifen, selective estrogen receptor modifiers [SERMs], diet, and exercise) likely to favorably influence breast cancer risk; for osteoporosis prevention, an array of strategies also are available, with some (bisphosphonates, tamoxifen, SERMs, and exercise) likely to favorably influence breast cancer risk.
CONCLUSION:

Current data preclude the generation of evidence-based guidelines for HRT use in breast cancer survivors, and clinical trials in this setting should be supported. However, given available therapeutic alternatives for menopausal symptom management and chronic disease prevention, breast cancer survivors should be offered HRT only with caution and with their full participation in the decision-making process.

In order to make a detailed analysis, we selected a group of 21 patients with the diagnosis of invasive breast cancer who had HRT after primary surgical treatment.

Each patient from the selected group was compared with two patients from the control group with the diagnosis of invasive breast cancer who did not have HRT after primary surgical treatment. The control cases were matched to selected HRT patients with regard to age at time of the diagnosis, year of diagnosis, diameter of the tumour, metastatic spread in the axillary lymph nodes, and disease-free interval until applying HRT. The same criteria were applied in all analyses. The data were analysed by odds ratio (OR) calculation with a confidence interval of 95%, taking into account residual malignancy and death due to breast cancer in both groups (including carcinoma in the contralateral breast).

RESULTS: HRT was applied in 21 patients treated for breast cancer.

In 33% of them, radical mastectomy revealed metastases in the axillary lymph nodes. Hormone receptors could not be found in 57% of patients. In the majority of patients the tumour measured 17.6mm in diameter.
HRT was started on average62 months (range 1-180 months) after diagnosis, and lasted an average of 28 months (range3 72 months). All 21 patients used oestradiol as HRT, i.e. a non-conjugated oestrogen.

Combined hormonal therapy (oestrogens + progestagens) was given to 95% of patients with median age of 47 years (range 41-59 years) at the beginning of HRT.

Relapse was observed in four patients (19%) of the HRT group; of these, one had a carcinoma of the contralateral breast.
In the control group, relapse was observed in five patients (11%); one of these five patients had a carcinoma of the contralateral breast.
In the HRT group, there were no deaths among the patients with confirmed relapse, while one patient died in the control group.

The estimated risk (OR= 1.74, 95%S CI 0.34-8.88) of relapse of breast cancer was calculated by comparing data from HRT users, who had received HRT for 28 months (range 3-72 months) on average, with data from the control group. The estimated risk of breast cancer relapse in HRT users who had been receiving HRT for less than 24 months was 0.65 (OR = 0.65, 95% CI 0.02-7.85).

CONCLUSION: Despite the inherent limitations of retrospective data and the need for prospective randomized trials to assess the possible influence of HRT on progression after breast cancer treatment, the present observations suggest that HRT treatment for less than 24 months does not appear to have a pronounced adverse effect on cancer outcome. Nevertheless, until appropriate clinical trials determine that HRT is safe, caution is needed.

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1998 Observational study- No increase in breast cancer recurrence after HRT
oral or transdermal estrogen and a progestin

Women who have been previously treated for breast cancer are usually advised to avoid hormone therapy for fear of increasing their risk of tumor recurrence. However, for some women, menopausal symptoms are so severe that their quality of life is poor. Because ethic committees are reticent to permit a double-blind randomized trial, we performed a cohort study of hormone therapy after breast cancer.
METHODS:

The study group comprised 1472 women with breast cancer. A total of 167 subjects had used an oral or transdermal estrogen after their treatment for breast cancer. Amongst these estrogen users, 152 (91%) had also used a progestin. In total, 106 other women had used a progestin alone as a treatment for menopausal flushes and not as a treatment for breast cancer. Cox regression analysis was performed using estrogen as a time-dependent covariate with disease-free interval as the outcome.

RESULTS:

The uncorrected hazard ratio for the estrogen-progestin users was 0.67 (95% confidence interval (CI) 0.38-1.16) and for the progestin alone users was 0.85 (95% CI 0.44-1.65).

CONCLUSIONS: This study was unable to demonstrate a significant increase in risk of breast cancer recurrence for women who used HRT and suggests that the time is now appropriate for a randomized prospective trial of hormone therapy after breast cancer.

We report our experience with 25 women previously treated for breast cancer who subsequently received hormone replacement therapy (HRT) for the relief of menopausal symptoms and the prevention of postmenopausal cardiovascular disease and osteoporosis.

Two patients had in situ disease, 13 had stage I disease, 7 had stage II disease, 1 had stage III disease, and 2 had invasive cancer of undetermined stage. Seventeen patients (group I) began HRT less than 24 months after primary breast cancer therapy, and 8 patients (group II) began HRT more than 24 months after breast cancer therapy. The HRT-free interval for group I patients averaged 7.9 months and for group II patients averaged 64.5 months. The average period of observation while receiving HRT for the entire group was 35.2 months (range: 24 to 82 months).

Three of 25 patients have had a recurrence, all in group I. One patient developed local recurrence after breast conservation treatment, and her condition was salvaged by further wide excision. Two patients developed recurrence after mastectomy, and one patient ultimately died of systemic disease. The overall survival rate for the entire group was 96%. Overall survival of high-risk group I patients, with a mean follow-up of 30.4 months, was 94%.

We recognize that this report of HRT in a small group of patients does not have the power to demonstrate an adverse effect of HRT on breast cancer. However, the lack of an obvious adverse effect of HRT in this group of breast cancer patients and the known beneficial effect of HRT on postmenopausal cardiovascular disease and osteoporosis warrant formal prospective trials of HRT in such patients.

To investigate the attitude of Greek obstetrician-gynaecologists towards prescription of hormone therapy to postmenopausal breast cancer survivors.
METHODS:An anonymous questionnaire was sent to members of the Hellenic Society of Obstetrics and Gynaecology with a hypothetical case and a series of relevant questions.
RESULTS:Three hundred valid answers were received. Hormone therapy would be prescribed to a breast cancer survivor by only 8%; 80% of these would prefer tibolone. In contrast, 92% would not prescribe hormone therapy; 97% would do so due to the risk of disease recurrence; 70% would not prescribe any alternative therapy, 21% would prescribe CNS-active compounds and 7% SERMs. CONCLUSIONS:The vast majority of Greek obstetrician-gynaecologists would not prescribe hormone therapy for menopausal symptoms in breast cancer survivors due to the theoretical risk of disease recurrence. Among those who would not prescribe hormone therapy, 21% would opt to CNS-active compounds.

To investigate how physicians felt about HRT use in breast cancer survivors a half year after the WHI trial.
METHODS:In December 2002, a questionnaire was conducted in Flanders (Belgium). The survey contained a presentation of a 35-year-old breast cancer survivor who presented with climacteric symptoms after treatment with tamoxifen.
RESULTS:With a response rate of 33.65%, a majority of the physicians did not prescribe classical oral HRT (5.40%) in this patient. Physicians prefer to prescribe tibolone (30.68%) or other alternative treatment (50.00%). The main reason was the fear for increased recurrence of breast cancer. Furthermore the WHI oestrogen plus progestin trial and its attention in the media, a half year prior to the survey, influenced one-third of the physician’s prescribing attitude. CONCLUSIONS:Two-thirds of the physicians did not change prescribing attitude after the WHI oestrogen plus progestin trial. HRT is a well proven effective treatment in breast cancer survivors with severe climacteric complaints, but a majority of physicians is not convinced of its safety in breast cancer survivors. Therefore, a majority of physicians do not find the need to prescribe HRT in breast cancer survivors.

The use of hormone therapy for climacteric symptoms in patients with breast cancer has become a significant and important point of discussion due in part to the improved survival from this disease in recent years. There is a theoretic risk that exogenous hormones will stimulate the growth of microscopic disease and lead to decreased survival and increased recurrence. In addition, 2 large studies have shown that there is an association between hormone therapy and breast cancer risk in women without an earlier history of breast cancer. Other studies suggest that estrogen alone may have a superior safety profile than estrogen and progesterone in combination. Hormone therapy could be justified for improvement of quality of life when other options have failed and the patient is informed of the risks.

Abstract The importance of addressing survivorship issues has been emphasised in recent years. As cancer therapies improve there is a growing population of cancer survivors, which includes many women with premature menopause. Women who are premenopausal at the time of their cancer diagnosis may have specific survivorship issues to be addressed, including infertility, early menopause and sexual dysfunction. These factors can continue have a significant impact on the quality of life of these patients at long term follow up. Data for this Review were identified by searches of MEDLINE, PubMed, and references from relevant articles using the search terms ‘HRT’, ‘women/female cancer/tumour’, ‘menopause’ and ‘survivorship’. Abstracts and reports from meetings were excluded. Only papers published in English between 1980 and 2010 were included.
The aims of this review are to:
• Address the hormonal factors which impact on cancer survivorship for premenopausal women
• Review the debate for the role of hormone replacement therapy (HRT) in cancer survivors
• Provide information for physicians and patients regarding the management of hormonally driven survivorship issues (for different tumour types), based on current evidence The recommendations for practice are that HRT may be offered for the alleviation of vasomotor symptoms in cancer survivors who undergo premature menopause up to the age of natural menopause (51 years in the UK). HRT (including vaginal oestrogen preparations) is contraindicated in survivors of oestrogen receptor positive breast cancer and low grade endometrial leiomyosarcoma, where non-HRT alternatives should be considered to alleviate symptoms.

Controversy exists regarding the safety of hormone replacement therapy (HRT) after a diagnosis of breast cancer. The objective of this study is to perform a matched cohort analysis to evaluate the impact of HRT on mortality in breast cancer survivors. Patients with breast cancer who received HRT after diagnosis of breast cancer were identified. Control subjects were identified from the regional cancer registry. Matching criteria included age at diagnosis, stage of breast cancer, and year of diagnosis. Controls were selected only if they were alive at the time of initiation of HRT of the matched case. Only subjects not included in a previously reported matched analysis were selected. One hundred twenty-five cases were matched with 362 controls. Ninety-eight percent (123/125) of the cases received systemic estrogen; 90/125 (72%) also received a progestational agent. The median interval between diagnosis of breast cancer and initiation of HRT was 46 months (range 0-401 months). The median duration of HRT was 22 months (range 1-357 months). The risk of death was lower among the HRT survivors; odds ratio 0.28 (95% confidence interval 0.11-0.71). This analysis does not suggest that HRT after the treatment of breast cancer is associated with an adverse outcome. _____________________________ ___________________________

PURPOSE: Breast cancer (BC) is the most frequent female carcinoma and the major cause of death in women aged 35–50 years. The total number of patients surviving BC and especially the morbidity rate of patients below the age of 55 years has increased significantly in the last several years. As a consequence, the number of BC patients suffering from the long-term effects of estrogen deficiency due to adjuvant treatment is increasing. At present, hormone replacement therapy (HRT) following BC treatment is applied individually and mainly depends on the severity of postmenopausal symptoms (PMS) experienced by these patients.
PATIENTS AND METHODS: In a retrospective study (total n = 185 BC patients, 64 with and 121 without HRT), the effect of HRT during or after adjuvant therapy [chemotherapy and/ or (anti-) hormonotherapy] has been investigated. The surveillance period was up to 60 months. Evaluated were HRT effects on (1) PMS measured by a comprehensive life quality questionnaire, (2) bone mineral density (BMD) measured by osteodensitometry and (3) morbidity as well as mortality rates. RESULTS: Both groups did not differ with regard to tumor stage, lymph node involvement, metastasis, grading, and steroid hormone receptor status. A reduction in PMS was significant in women taking HRT (p < 0.001), especially in the subgroup of women < or =50 years (p < 0.0001). For both age groups, the median reduction in BMD (z-score) was less in women receiving HRT (< or =50 years: without HRT -1.99 vs. with HRT -0.95, p < 0.05; >50 years: without HRT -2.29 vs. with HRT -1.19, p < 0.01). There were no statistically significant differences regarding morbidity and mortality (p = 0.29). CONCLUSION: In this study of BC patients, the use of HRT shows positive effects on PMS and BMD. There was no significant influence on morbidity or mortality. However, a reevaluation of HRT in the routine management of BC patients should await the results of prospective randomized trials. Copyright 2001 S. Karger AG, Basel

PURPOSE: To determine whether estrogen replacement therapy (ERT) alters the development of new or recurrent breast cancer in women previously treated for localized breast cancer.
PATIENTS AND METHODS: Potential participants (n = 319) in a trial of ERT after breast cancer were observed prospectively for at least 2 years whether they enrolled onto the randomized trial or not. Of 319 women, 39 were given estrogen and 280 were not given hormones. Tumor size, number of lymph nodes, estrogen receptors, menopausal status at diagnosis, and disease-free interval at the initiation of the observation period were comparable for the trial participants (n = 62) versus nonparticipants (n = 257) and for women on ERT (n = 39) versus controls (n = 280). Cancer events were ascertained for both groups.
RESULTS: Patient and disease characteristics were comparable for the trial participants versus nonparticipants, as well as for the women on ERT versus the controls. One patient in the ERT group developed a new lobular estrogen receptor-positive breast cancer 72 months after the diagnosis of a ductal estrogen receptor-negative breast cancer and 27 months after initiation of ERT. In the control group, there were 20 cancer events: 14 patients developed new or recurrent breast cancer at a median time of 139.5 months after diagnosis and six patients developed other cancers at a median time of 122 months.

CONCLUSION: ERT does not seem to increase breast cancer events in this subset of patients previously treated for localized breast cancer. Results of randomized trials are needed before any changes in current standards of care can be proposed. ___________________________

OBJECTIVE: Our purpose was to measure any adverse effect (if one exists) of hormone replacement therapy administered to breast cancer survivors. STUDY DESIGN: Forty-one patients from a group of 77 patients who received hormone replacement therapy after therapy for breast cancer were matched with 82 comparison patients not receiving hormone replacement therapy. Both groups were taken from the same population on the basis of cancer registry of the Cancer Surveillance Program of Orange County and were compared with regard to survival results.
RESULTS: An analysis of survival time and disease-free time revealed no statistically significant difference between the two groups.

CONCLUSIONS: No obvious adverse effect of hormone replacement therapy could be shown in this pilot study. A case is made for a prospective randomized trial. __________________________ ___________________________

OBJECTIVE: Most physicians believe that estrogen replacement therapy is contraindicated once a patient is diagnosed with breast cancer. Recently, several studies have shown that estrogen replacement therapy may be safely used in patients with early breast cancer that has been treated successfully. These women can have severe menopausal symptoms and are at risk for osteoporosis. We reviewed the current status of women in our practice with breast cancer who received estrogen replacement therapy, who did not receive hormone replacement therapy, and who did not receive estrogenic hormone replacement therapy. STUDY DESIGN: The study group consisted of 123 women (mean age, 65.4 +/- 8.85 years) who were diagnosed with breast cancer in our practice, including 69 patients who received estrogen replacement therapy for < or = 32 years after diagnosis. The comparative groups were 22 women who used nonestrogenic hormones for < or = 18 years and 32 women who used no hormones for < or = 12 years. The group who did not receive estrogenic hormone replacement therapy received androgens with or without progestogens (such as megestrol acetate). Of the 63 living hormone users, 56 women are still being treated in our clinic, as are 15 of the 22 subjects who receive nonestrogenic hormone replacement therapy. Follow-up was done through the tumor registry at University Hospital; those patients whose tumor records were not current were contacted by telephone. RESULTS: There were 18 deaths in the 123 patients: 6 patients who received estrogen replacement therapy (8.69%), 2 patients who received nonestrogenic hormone replacement therapy (9.09%), and 10 patients who received no hormone replacement therapy (31.25%). Of the 18 deaths, 9 deaths were from breast cancer (mortality rate, 7.3%); 3 deaths were from lung cancer; 1 death was from endometrial cancer; 1 death was from myocardial infarction; 1 death was from renal failure; and 3 deaths were from cerebrovascular accidents. The 9 deaths from breast cancer included one patient who received nonestrogenic hormone replacement therapy (mortality rate, 4.5%), 6 patients who received no hormone replacement therapy (mortality rate, 11.3%), and 2 patients who received estrogen replacement therapy (mortality rate, 4.28%). The 9 non- breast cancer deaths included 4 patients who received estrogen replacement therapy (endometrial cancer [1 death], lung cancer [1 death], cerebrovascular accident [1 death], and renal failure [1 death]), 1 patient who did not receive estrogenic hormone replacement therapy group (myocardial infarction), and 4 patients who used no hormones (lung cancer, 2 deaths; stroke, 2 deaths). Carcinoma developed in one patient in the estrogen replacement therapy group in the contralateral breast after 4 years of hormone replacement therapy; she is living and well 2.5 years later with no evidence of disease. Metastatic breast cancer developed in one patient after 8 years of hormone replacement therapy; she is living with disease. CONCLUSION: Estrogen replacement therapy apparently does not increase either the risk of recurrence or of death in patients with early breast cancer. These patients may be offered estrogen replacement therapy after a full explanation of the benefits, risks, and controversies. ___________________________

Clinical and experimental studies indicate that combined unique conjugated estrogens and medroxyprogesterone acetate moderately increase the risk of breast cancer in postmenopausal women. Classically, hormone replacement therapy is contra-indicated in women with a past history of breast cancer due to the fear of recurrence. However, these postmenopausal patients complain about hot flushes and adjuvant hormonal therapies (such as aromatase inhibitors, SERMs and Tamoxifen…) aggravate their symptoms. “Observational studies and their meta-analyses do not show a deleterious effect but rather a beneficial impact of hormone replacement therapy among women with a past history of breast cancer.” We summarise all these studies and their biological, clinical and epidemiological interpretations. We conclude that short term hormone replacement therapy is safe among those women requesting a replacement therapy after complete information. It is however advisable to conclude definitely only when prospective randomised trials with estradiol or tibolone (a promising alternative) will be available. Such ongoing studies will allow to conclude definitely the possible benefits and risks of hormone replacement therapy among patients with a past history of breast cancer.
__________________________

Int J Gynaecol Obstet. 1999 Jan;64(1):59-63.

Estrogen replacement therapy in breast cancer survivors.

Guidozzi F. Department of Obstetrics and Gynaecology, Johannesburg Hospital, University of the Witwatersrand Medical School, South Africa.
OBJECTIVE: To determine whether estrogen replacement therapy (ERT) adversely affected outcome of breast cancer survivors.
METHOD: A prospective descriptive study of all breast cancer survivors who requested ERT because of intractable menopausal symptoms. All patients presented voluntarily as gynecological outpatients and were all given oral continuous opposed ERT: 20 premarin and medroxyprogesterone and four tibolone. RESULTS: Twenty-four patients who had previously been treated for breast cancer 8-91 months prior to their initiating ERT have been observed for 24-44 months. There were 15 patients with stage 1, eight with stage 2 and one with stage 4 breast cancer. The mean age of the patients at commencement of ERT was 48 years (range 42-61). Two patients had a biopsy of a suspicious breast nodule: both of which were benign. There have not been any recurrences to date.

CONCLUSION: Breast cancer survivors did not have their outcome adversely affected by ERT during an observation period of 24-44 months

Health care professionals in modern Western societies will meet an increasing number of women surviving breast cancer. How the menopause of these women should be treated is still an open question. Use of hormone replacement therapy (HRT) may, at least in theory, increase the risk for recurrence of cancer, but its categoric refusal is a double-edged sword because it also denies these women all the indisputable health benefits HRT provides. This refusal is not, however, supported by the observational data available so far on this question, because HRT has not increased the risk for breast cancer recurrence. In fact, it is well established that HRT abolishes hot flushes and improves significantly these patients’ quality of life. At present, we have no effective nonhormonal alternatives for the control of vasomotor symptoms, and the efficacy of phytoestrogens in the treatment of menopausal symptoms is unproven. Selective estrogen receptor modulators (SERMs) which protect against osteoporosis and perhaps also against breast cancer, and which may have beneficial effects on the cardiovascular system, aggravate hot flushes and are therefore not useful, at least in the first postmenopausal years. In some countries, progestins are often prescribed for the control of such patients’ vasomotor symptoms, but their safety has never been assessed in clinical trials, and in theory they can be harmful. Randomized clinical trials (RCT) on the use of HRT in breast cancer survivors are underway, but their completion will take years, and even these may be open to criticism. Tibolone may appear to be an appealing alternative for HRT, but it should also be studied with RCTs in this indication. At present, a patient with a history of breast cancer must be given balanced information as to the possible benefits and risks of HRT, and she herself must make the decision whether or not to start HRT.

OBJECTIVE: To evaluate the outcome of breast cancer patients who elected estrogen replacement therapy (ERT).
STUDY DESIGN: Breast cancer survivors who elected ERT received the preferred regimen of conjugated estrogen 0.625 mg/day with medroxyprogesterone acetate 2.5 mg/day.
RESULTS: 145 patients received ERT for at least 3 months. Thirteen recurrences (9%) were identified; 10 are alive with disease, 3 are dead of disease. The median interval between diagnosis and commencement of ERT was 41 months. Forty-one percent of the study group initiated ERT within 3 years of their breast cancer diagnosis. The median duration of follow-up on ERT was 30 months.

CONCLUSION: The concern that ERT might activate growth in occult metastatic sites and promote a rash of recurrences was not confirmed. It is unreasonable to categorically deny all breast cancer survivors ERT.

Even though it is accepted that women with breast cancer should not receive estrogen therapy, doubts have been expressed as to the validity of this policy. In recent years opposition to this practice has been voiced more adamantly. The results of the Women’s Health Initiative (WHI) study, published in July 2002,question the safety margin of estrogen therapy (ET) or hormone therapy (HT) in menopause. Whether this concern is applicable to breast cancer survivors is unclear as these women were not addressed bythe study. In light of the uncertainties raised by the study and particularly the ongoing controversy about breast cancer patients, a review of the literature published prior to March 2003 was undertaken. The information gathered on the topic comes from 10 uncontrolled studies and 11 case-controlled studies, 8retrospective and 3 prospective, carried out over the past decade.

The experience encompasses 1,558 breast cancer survivors treated with ET or HT. Overall, the recurrence rate accrued from the uncontrolled studies is 7.3% (53 of 728). The average rate culminating from 11 case-controlled studies is 10.7% (99 of 830) (2.6-15.4%) in treated patients vs. 20.3% (739 of 3,640) (2.3-29.5%) in their untreated counterparts.

This review revealed no increase in recurrent disease among treated patients but is not conclusive as some studies that have been flawed by biases and confounders. The fact that only 2 studies were case controlled and prospective as well as randomized, and considering concerns raised by the WHI study, it seems that many more such trials will be necessary before this controversial issue will be settled

BACKGROUND: In the United States, estrogen replacement therapy (ERT) is discouraged in breast cancer survivors because of concerns that hormones may reactivate the disease. Because ERT can improve quality of life and decrease morbidity from osteoporosis and cardiovascular disease, however, this policy is increasingly being challenged.

METHODS: From February to August 1995, 607 breast cancer survivors were interviewed concerning ERT usage. Sixty-four patients indicated they received some form of ERT after their breast cancer diagnosis. Medical records for these patients were analyzed for disease stage, surgical treatment, adjuvant treatment, estrogen and progesterone receptor status, date of initiation of ERT, type of ERT, recurrence, and final outcome. Patients receiving ERT were followed prospectively. RESULTS: Eight patients were excluded because they had used only vaginal cream ERT. The remaining 56 received ERT as conjugated estrogens, an estradiol patch, estropipate, or birth control pills. The median follow-up from diagnosis was 12.8 years (range, 4.7-38.9 years). The median time on ERT since diagnosis was 6.4 years (range, 1.0-20.9 years); 38% of the patients initiated ERT within 2 years of diagnosis. Estrogen receptors were positive in 28 (74%) of the 38 cases with available information. Pathological disease stage at time of diagnosis and treatment was 0 in 15 cases (27%), I in 27 (48%), and II in 14 (25%). Twenty-six patients (47%) received adjuvant chemotherapy or hormonal therapy. One local recurrence and one contralateral breast cancer occurred during the follow-up period (13.5 and 9.6 years, respectively), with no regional or distant recurrences, for a 15-year actuarial disease-free survival rate of 92.5%. There were no breast cancer deaths.
CONCLUSIONS: Use of ERT in a cohort of breast cancer survivors with tumors of generally good prognosis was not associated with increased breast cancer events compared with non-ERT users, even over a long follow-up period.

The influence of estrogens on the growth of mammary carcinoma cell lines has been confirmed by many studies. Therefore, past or recent history of breast cancer is principally seen as a contraindication for estrogen or estrogen/progestin replacement therapy. The recently made possible early diagnosis of mammary carcinomas in many cases has resulted in a better prognosis, and means that following treatment women are living for a long time postmenopausally.

Therefore, hormone replacement therapy is demanded by many patients. Recent studies with a limited number of patients, however, have shown no adverse effects of an estrogen or an estrogen-progestin replacement therapy after treatment of a mammary carcinoma. In some studies even a positive effect has been found in recurrence free survival. However, a final decision upon estrogen or estrogen/progestin replacement therapy in postmenopausal women with a history of breast cancer, cannot be made until the results of prospective clinical trials are finalized.

OBJECTIVE: We prospectively administered estrogen replacement therapy (ERT) to control estrogen deficiency symptoms in breast cancer survivors as part of our clinical practice. We report the consequences of ERT compared with a historical matched-control group.

DESIGN: Two hundred seventy-seven disease-free survivors received ERT. Controls were matched for exact stage, a recurrence-free period similar to the period to ERT initiation in the ERT group, approximate age, and duration of follow-up.

The mean time from breast cancer diagnosis to initiation of ERT was 3.61 (+/- 0.25) years, with a median of 1.88 years.

The mean duration of ERT was 3.7 (+/- 3.01) years, with a median of 3.05 years.

The ERT group was more likely to be estrogen receptor negative (P = 0.01), to have received prior ERT (P < 0.001), and to have received no adjuvant tamoxifen (P < 0.001). There was no significant difference between the ERT and control groups in ipsilateral primary/recurrence (5/155 v 5/143; P = 0.85), contralateral breast cancers (10/258 v 9/260; P = 0.99), or systemic metastasis (8/277 v 15/277; P = 0.13). Noncause-specific deaths in the control group numbered 15 (of 277), and in the ERT group, 7 (of 277) (P = 0.03). Overall survival favored the ERT group (P = 0.02).

CONCLUSIONS: In these selected patients, ERT relieved estrogen deficiency symptoms and did not increase the rate or time to an ipsilateral recurrence/new primary, contralateral new primary, local-regional recurrence, or systemic metastases. –

Bioidenticall_hormones_breast_tumor_postmenopausal_mouse_2014Reproductive Biology and Endocrinology 2014, 12:66 Published: 15 July 2014
The role of hormones and aromatase inhibitors on breast tumor growth and general health in a postmenopausal mouse model
Arunkumar Arumugam1 Elaine A Lissner2 Rajkumar Lakshmanaswamy1*

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I read here you believe Estrogen has a protective quality. I believe Dr Lee in “what your Doc won’t tell you about breast Cancer” says Progesterone has a protective quality. Instead of tamaxafin for 5 years I am thinking I can take Bioidentical Progesterone. As I thought Progesterone helps cells to diffferentiate. Is that correct? my cream is progesterone 100.0mg/1.0Gm
Pregnenolone 25.0mg/1.0Gm
I am ER+PR+HER2+